dna damage


Summary: Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.

Top Publications

  1. ncbi Cellular senescence in cancer and aging
    Manuel Collado
    Spanish National Cancer Research Center CNIO, Madrid, Spain
    Cell 130:223-33. 2007
  2. pmc The DNA damage response: making it safe to play with knives
    Alberto Ciccia
    Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 40:179-204. 2010
  3. pmc The DNA-damage response in human biology and disease
    Stephen P Jackson
    The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
    Nature 461:1071-8. 2009
  4. ncbi Requirement for p53 and p21 to sustain G2 arrest after DNA damage
    F Bunz
    The Howard Hughes Medical Institute and The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231, USA
    Science 282:1497-501. 1998
  5. ncbi A DNA damage checkpoint response in telomere-initiated senescence
    Fabrizio d'Adda di Fagagna
    1 The Wellcome Trust Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, UK 2 Present address IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
    Nature 426:194-8. 2003
  6. ncbi p53 in health and disease
    Karen H Vousden
    Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
    Nat Rev Mol Cell Biol 8:275-83. 2007
  7. ncbi Genome maintenance mechanisms for preventing cancer
    J H Hoeijmakers
    MGC Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus University, PO Box 1738, 3000DR Rotterdam, The Netherlands
    Nature 411:366-74. 2001
  8. ncbi ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
    Shuhei Matsuoka
    Department of Genetics and Center for Genetics and Genomics, Brigham and Women s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Science 316:1160-6. 2007
  9. doi Modulation of microRNA processing by p53
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Nature 460:529-33. 2009
  10. doi An oncogene-induced DNA damage model for cancer development
    Thanos D Halazonetis
    Department of Molecular Biology and Department of Biochemistry, University of Geneva, CH 1205 Geneva, Switzerland
    Science 319:1352-5. 2008

Detail Information

Publications289 found, 100 shown here

  1. ncbi Cellular senescence in cancer and aging
    Manuel Collado
    Spanish National Cancer Research Center CNIO, Madrid, Spain
    Cell 130:223-33. 2007
    ..by multiple mechanisms including telomere shortening, the epigenetic derepression of the INK4a/ARF locus, and DNA damage. Together these mechanisms limit excessive or aberrant cellular proliferation, and so the state of senescence ..
  2. pmc The DNA damage response: making it safe to play with knives
    Alberto Ciccia
    Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 40:179-204. 2010
    ..To respond to these threats, eukaryotes have evolved the DNA damage response (DDR)...
  3. pmc The DNA-damage response in human biology and disease
    Stephen P Jackson
    The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
    Nature 461:1071-8. 2009
    ..To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair...
  4. ncbi Requirement for p53 and p21 to sustain G2 arrest after DNA damage
    F Bunz
    The Howard Hughes Medical Institute and The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231, USA
    Science 282:1497-501. 1998
    After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle...
  5. ncbi A DNA damage checkpoint response in telomere-initiated senescence
    Fabrizio d'Adda di Fagagna
    1 The Wellcome Trust Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, UK 2 Present address IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
    Nature 426:194-8. 2003
    ..These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1...
  6. ncbi p53 in health and disease
    Karen H Vousden
    Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
    Nat Rev Mol Cell Biol 8:275-83. 2007
    ..Although the function of p53 as a tumour suppressor ensures that we can't live without it, an integrated view of p53 suggests that not all of its functions are conducive to a long and healthy life...
  7. ncbi Genome maintenance mechanisms for preventing cancer
    J H Hoeijmakers
    MGC Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus University, PO Box 1738, 3000DR Rotterdam, The Netherlands
    Nature 411:366-74. 2001
    ..This review summarizes the main DNA caretaking systems and their impact on genome stability and carcinogenesis...
  8. ncbi ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
    Shuhei Matsuoka
    Department of Genetics and Center for Genetics and Genomics, Brigham and Women s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Science 316:1160-6. 2007
    Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related)...
  9. doi Modulation of microRNA processing by p53
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Nature 460:529-33. 2009
    ..of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the ..
  10. doi An oncogene-induced DNA damage model for cancer development
    Thanos D Halazonetis
    Department of Molecular Biology and Department of Biochemistry, University of Geneva, CH 1205 Geneva, Switzerland
    Science 319:1352-5. 2008
    Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation...
  11. ncbi Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
    Shideng Bao
    Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nature 444:756-60. 2006
    ..Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity...
  12. ncbi DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
    Jirina Bartkova
    Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK 2100 Copenhagen, Denmark
    Nature 434:864-70. 2005
    ..lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53...
  13. pmc DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence
    Olga V Leontieva
    Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC, L3 312, Elm and Carlton Streets, Buffalo, NY 14263, USA
    Aging (Albany NY) 2:924-35. 2010
    ..We conclude that induction of p53 does not activate the senescence program in quiescent cells. In cells with induced p53, re-activation of mTOR by serum stimulation causes senescence, as an equivalent of cellular growth...
  14. doi Genomic instability--an evolving hallmark of cancer
    Simona Negrini
    Department of Molecular Biology, CH 1205 Geneva, Switzerland
    Nat Rev Mol Cell Biol 11:220-8. 2010
    ..cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.
  15. ncbi A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
    T T Paull
    Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0540, USA
    Curr Biol 10:886-95. 2000
    ..Recently it has been reported that a member of the histone H2A family, H2AX, becomes extensively phosphorylated within 1-3 minutes of DNA damage and forms foci at break sites.
  16. pmc How telomeres solve the end-protection problem
    Titia de Lange
    Laboratory of Cell Biology and Genetics, Rockefeller University, New York, NY 10021, USA
    Science 326:948-52. 2009
    ..have the potential to be mistaken for damaged or broken DNA and must therefore be protected from cellular DNA damage response pathways...
  17. pmc 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers
    Peter Bouwman
    Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    Nat Struct Mol Biol 17:688-95. 2010
    ..We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings...
  18. pmc Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
    Francis Rodier
    Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA
    Nat Cell Biol 11:973-9. 2009
    ..Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs)...
  19. doi How shelterin protects mammalian telomeres
    Wilhelm Palm
    Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA
    Annu Rev Genet 42:301-34. 2008
    ..contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage response and regulates telomere maintenance by telomerase...
  20. ncbi DNA damage foci at dysfunctional telomeres
    Hiroyuki Takai
    Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA
    Curr Biol 13:1549-56. 2003
    We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells...
  21. pmc Significance analysis of microarrays applied to the ionizing radiation response
    V G Tusher
    Departments of Medicine and Biochemistry, Stanford University, 269 Campus Drive, Center for Clinical Sciences Research 1115, Stanford, CA 94305-5151, USA
    Proc Natl Acad Sci U S A 98:5116-21. 2001
    ..Surprisingly, four nucleotide excision repair genes were induced, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation...
  22. doi Transcriptional control of human p53-regulated genes
    Todd Riley
    The Institute for Advanced Study, Princeton, New Jersey, USA
    Nat Rev Mol Cell Biol 9:402-12. 2008
    ..Following DNA damage, p53 regulates key processes, including DNA repair, cell-cycle arrest, senescence and apoptosis, in order to ..
  23. ncbi Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
    Raul Mostoslavsky
    Howard Hughes Medical Institute, The Children s Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
    Cell 124:315-29. 2006
    ..Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER)...
  24. ncbi A microRNA component of the p53 tumour suppressor network
    Lin He
    Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
    Nature 447:1130-4. 2007
    ..Genes encoding miRNAs in the miR-34 family are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo...
  25. ncbi Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)
    Utz Herbig
    Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
    Mol Cell 14:501-13. 2004
    ..Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 ..
  26. doi 53BP1-mediated DNA double strand break repair: insert bad pun here
    Angela T Noon
    Southern Alberta Cancer Research Institute, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N4N1
    DNA Repair (Amst) 10:1071-6. 2011
    53BP1 is an established player in the cellular response to DNA damage and is a canonical component of ionizing-radiation induced foci--that cadre of proteins which assemble at DNA double strand breaks following radiation exposure and ..
  27. ncbi Tumor spectrum analysis in p53-mutant mice
    T Jacks
    Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139
    Curr Biol 4:1-7. 1994
    ..The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of ..
  28. doi Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer
    Martin F Lavin
    Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia
    Nat Rev Mol Cell Biol 9:759-69. 2008
  29. pmc The ATM protein kinase and cellular redox signaling: beyond the DNA damage response
    Scott Ditch
    The Howard Hughes Medical Institute, The Department of Molecular Genetics and Microbiology, The University of Texas at Austin, Austin, TX 78712, USA
    Trends Biochem Sci 37:15-22. 2012
    The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its role in the DNA damage response, but recent findings suggest that it also functions as a redox sensor that controls the levels of reactive oxygen species in ..
  30. ncbi Cisplatin: mode of cytotoxic action and molecular basis of resistance
    Zahid H Siddik
    Department of Experimental Therapeutics, Unit 104, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 4009, USA
    Oncogene 22:7265-79. 2003
    ..b>DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of ..
  31. ncbi Shelterin: the protein complex that shapes and safeguards human telomeres
    Titia de Lange
    The Rockefeller University, New York, New York 10021, USA
    Genes Dev 19:2100-10. 2005
    ..proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance ..
  32. doi Tumour suppression by p53: a role for the DNA damage response?
    David W Meek
    Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
    Nat Rev Cancer 9:714-23. 2009
    ..This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression ..
  33. pmc The p53 network: cellular and systemic DNA damage responses in aging and cancer
    H Christian Reinhardt
    Cologne Excellence Cluster on Cellular Stress Response in Aging Associated Diseases, University of Cologne, 50674 Cologne, Germany
    Trends Genet 28:128-36. 2012
    ..b>DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-..
  34. pmc Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair
    Eva Petermann
    Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
    Mol Cell 37:492-502. 2010
    ..In conclusion, our data suggest that restart of stalled replication forks and HR repair of collapsed replication forks require two distinct RAD51-mediated pathways...
  35. ncbi Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1
    Eros Lazzerini Denchi
    Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
    Nature 448:1068-71. 2007
    ..However, because telomere attrition is accompanied by secondary DNA damage, it has remained unclear whether there is an ATM-independent pathway for the detection of damaged telomeres...
  36. ncbi Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family
    S Keeney
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
    Cell 88:375-84. 1997
    ..The S. pombe homolog, rec12p, is also known to be required for meiotic recombination. Thus, these findings provide direct evidence that the mechanism of meiotic recombination initiation is evolutionarily conserved...
  37. pmc Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence
    Graeme Hewitt
    Ageing Research Laboratories, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
    Nat Commun 3:708. 2012
    ..Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells...
  38. pmc DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
    M A Kang
    Department of Molecular Biosciences, IBIS Program, Northwestern University, Evanston, IL 60201, USA
    Cell Death Dis 3:e249. 2012
    The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated...
  39. ncbi Cellular processing of platinum anticancer drugs
    Dong Wang
    Department of Chemistry, Massachusetts Institute of Technology, Room 18 498, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
    Nat Rev Drug Discov 4:307-20. 2005
    ..are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death...
  40. pmc DNA interstrand crosslink repair and cancer
    Andrew J Deans
    London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms EN63LD, UK
    Nat Rev Cancer 11:467-80. 2011
    ..Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance...
  41. ncbi DRAM, a p53-induced modulator of autophagy, is critical for apoptosis
    Diane Crighton
    Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
    Cell 126:121-34. 2006
    ..Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death...
  42. pmc PARP inhibition: PARP1 and beyond
    Michele Rouleau
    Laval University Medical Research Center, Laval University, Quebec, Canada
    Nat Rev Cancer 10:293-301. 2010
  43. ncbi Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
    Jirina Bartkova
    Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK 2100 Copenhagen, Denmark
    Nature 444:633-7. 2006
    ..One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-..
  44. ncbi Cellular senescence: when bad things happen to good cells
    Judith Campisi
    Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA
    Nat Rev Mol Cell Biol 8:729-40. 2007
  45. pmc Y-family DNA polymerases and their role in tolerance of cellular DNA damage
    Julian E Sale
    Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
    Nat Rev Mol Cell Biol 13:141-52. 2012
    ..However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieved...
  46. ncbi DNA double-strand breaks: signaling, repair and the cancer connection
    K K Khanna
    The Queensland Institute of Medical Research, and Department of Pathology, University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia
    Nat Genet 27:247-54. 2001
    ..Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and ..
  47. ncbi Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
    Hannah Farmer
    Cancer Research UK Gene Function and Regulation Group, London, UK
    Nature 434:917-21. 2005
    ..These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer...
  48. pmc Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress
    Johnny M Tkach
    Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
    Nat Cell Biol 14:966-76. 2012
    Relocalization of proteins is a hallmark of the DNA damage response...
  49. doi Regulation of DNA damage responses by ubiquitin and SUMO
    Stephen P Jackson
    The Gurdon Institute and the Department of Biochemistry, University of Cambridge, Cambridge, UK
    Mol Cell 49:795-807. 2013
    ..review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels...
  50. ncbi Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints
    Aziz Sancar
    Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 7260, USA
    Annu Rev Biochem 73:39-85. 2004
    b>DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death...
  51. doi The DNA damage response and cancer therapy
    Christopher J Lord
    The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
    Nature 481:287-94. 2012
    ..instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is ..
  52. pmc XRCC3 promotes homology-directed repair of DNA damage in mammalian cells
    A J Pierce
    Cell Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA
    Genes Dev 13:2633-8. 1999
    Homology-directed repair of DNA damage has recently emerged as a major mechanism for the maintenance of genomic integrity in mammalian cells. The highly conserved strand transferase, Rad51, is expected to be critical for this process...
  53. pmc p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling
    Andrei V Budanov
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0723, La Jolla, CA 92093, USA
    Cell 134:451-60. 2008
    ..Correspondingly, Sestrin2-deficient mice fail to inhibit mTOR signaling upon genotoxic challenge. Sestrin1 and Sestrin2 therefore provide an important link between genotoxic stress, p53 and the mTOR signaling pathway...
  54. ncbi Poly(ADP-ribose): novel functions for an old molecule
    Valerie Schreiber
    Département Intégrité du Génome de l UMR 7175, Centre National de la Recherche Scientifique, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard S Brant, BP 10413, F 67412 Illkirch cedex, France
    Nat Rev Mol Cell Biol 7:517-28. 2006
    ..These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism...
  55. doi Mutation of the RAD51C gene in a Fanconi anemia-like disorder
    Fiona Vaz
    Department of Medical and Molecular Genetics, King s College London School of Medicine, Guy s Hospital, London, UK
    Nat Genet 42:406-9. 2010
    ..The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the ..
  56. pmc MicroRNAs: new players in the DNA damage response
    Hailiang Hu
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1732, USA
    J Mol Cell Biol 3:151-8. 2011
    The DNA damage response (DDR) is a signal transduction pathway that decides the cell's fate either to repair DNA damage or to undergo apoptosis if there is too much damage...
  57. pmc Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair
    Agata Smogorzewska
    Department of Genetics, Howard Hughes Medical Institute, Center for Genetics and Genomics, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cell 129:289-301. 2007
    ..associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. Like FANCD2, FANCI is monoubiquitinated and unexpectedly, ubiquitination of each protein is important for the ..
  58. ncbi Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis
    Marzena Bienko
    Institute for Biochemistry II, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt, Germany
    Science 310:1821-4. 2005
    Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication ..
  59. pmc Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation
    Marzia Fumagalli
    IFOM Foundation FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
    Nat Cell Biol 14:355-65. 2012
    ..mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells...
  60. ncbi Activation of the ATM kinase by ionizing radiation and phosphorylation of p53
    C E Canman
    The Johns Hopkins School of Medicine, Oncology Center, Baltimore, MD 21205, USA
    Science 281:1677-9. 1998
    ..These observations, along with the fact that phosphorylation of p53 on serine-15 in response to ionizing radiation is reduced in ataxia telangiectasia cells, suggest that ATM is a protein kinase that phosphorylates p53 in vivo...
  61. pmc Small-molecule-induced DNA damage identifies alternative DNA structures in human genes
    Raphaël Rodriguez
    Department of Chemistry, University of Cambridge, Cambridge, UK
    Nat Chem Biol 8:301-10. 2012
    ..pyridostatin promotes growth arrest in human cancer cells by inducing replication- and transcription-dependent DNA damage. A chromatin immunoprecipitation sequencing analysis of the DNA damage marker γH2AX provided the genome-wide ..
  62. pmc GammaH2AX and cancer
    William M Bonner
    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
    Nat Rev Cancer 8:957-67. 2008
    ..Using gammaH2AX detection to determine the extent of DSB induction may help to detect precancerous cells, to stage cancers, to monitor the effectiveness of cancer therapies and to develop novel anticancer drugs...
  63. ncbi Free radicals, metals and antioxidants in oxidative stress-induced cancer
    M Valko
    Faculty of Chemical and Food Technology, Slovak Technical University, SK 812 37 Bratislava, Slovakia
    Chem Biol Interact 160:1-40. 2006
    ..It appears that the DNA damage is predominantly linked with the initiation process...
  64. ncbi Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes
    Lee Zou
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Science 300:1542-8. 2003
    ..ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication protein A (RPA), a protein complex that associates with single-stranded DNA (..
  65. pmc Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis
    Tsung Cheng Chang
    The McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Mol Cell 26:745-52. 2007
    ..Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in ..
  66. pmc The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
    Stephan Gasser
    Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, California 94720 3200, USA
    Nature 436:1186-90. 2005
    ..in non-tumour cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ATM (ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related) protein ..
  67. ncbi Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing
    R R Tice
    Integrated Laboratory Systems, Research Triangle Park, North Carolina 27709, USA
    Environ Mol Mutagen 35:206-21. 2000
    ..tests, the advantages of the SCG assay include its demonstrated sensitivity for detecting low levels of DNA damage, the requirement for small numbers of cells per sample, its flexibility, its low costs, its ease of application, ..
  68. ncbi Enhanced phosphorylation of p53 by ATM in response to DNA damage
    S Banin
    Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel
    Science 281:1674-7. 1998
    ..ATM phosphorylated p53 in vitro on a single residue, serine-15, which is phosphorylated in vivo in response to DNA damage. This activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug; the total ..
  69. pmc Pathways of DNA double-strand break repair during the mammalian cell cycle
    Kai Rothkamm
    Fachrichtung Biophysik, Universitat des Saarlandes, D 66421 Homburg Saar, Germany
    Mol Cell Biol 23:5706-15. 2003
    ..These data provide the first evaluation of the cell cycle-specific contributions of NHEJ and HR to the repair of radiation-induced versus replication-associated DSBs...
  70. ncbi Oxidative DNA damage: mechanisms, mutation, and disease
    Marcus S Cooke
    Oxidative Stress Group, Department of Clinical Biochemistry, University of Leicester, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, LE2 7LX, UK
    FASEB J 17:1195-214. 2003
    Oxidative DNA damage is an inevitable consequence of cellular metabolism, with a propensity for increased levels following toxic insult...
  71. doi 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress
    Claudia Lukas
    Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK 2100 Copenhagen, Denmark
    Nat Cell Biol 13:243-53. 2011
    ..Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations...
  72. doi DNA damage checkpoints in stem cells, ageing and cancer
    Tobias Sperka
    Leibniz Institute for Age Research Fritz Lipmann Institute, Beutenbergstr 11, 07745 Jena, Germany
    Nat Rev Mol Cell Biol 13:579-90. 2012
    b>DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16(INK4a) and p19(ARF)) and downstream targets (p21, ..
  73. doi DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis
    Wynand P Roos
    Department of Toxicology, University of Mainz, Obere Zahlbacher Str 67, D 55131 Mainz, Germany
    Cancer Lett 332:237-48. 2013
    ..Transcriptional inhibition may also contribute to apoptosis. Cells are equipped with sensors that detect DNA damage and relay the signal via kinases to executors, who on their turn evoke a process that inhibits cell cycle ..
  74. doi Maintaining genome stability at the replication fork
    Dana Branzei
    Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM IEO Campus, Via Adamello 16, 20139 Milan, Italy
    Nat Rev Mol Cell Biol 11:208-19. 2010
    ..These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle ..
  75. pmc Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint
    Q Liu
    Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA
    Genes Dev 14:1448-59. 2000
    ..of a conditional CHK1-deficient cell line, we demonstrate that ES cells lacking Chk1 have a defective G(2)/M DNA damage checkpoint in response to gamma-irradiation (IR)...
  76. doi More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance
    Jiri Lukas
    Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK 2100 Copenhagen, Denmark
    Nat Cell Biol 13:1161-9. 2011
    Following the discovery in 1998 of γ-H2AX, the first histone modification induced by DNA damage, interest in the changes to chromatin induced by DNA damage has exploded, and a vast amount of information has been generated...
  77. doi The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer
    Joanne Smith
    Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK
    Adv Cancer Res 108:73-112. 2010
    b>DNA damage is a key factor both in the evolution and treatment of cancer...
  78. ncbi hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase
    H Vaziri
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Cell 107:149-59. 2001
    b>DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis. We show here that the protein product of the gene hSIR2(SIRT1), the human homolog of the S...
  79. ncbi DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
    Christopher J Bakkenist
    Department of Hematology Oncology, St Jude Children s Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA
    Nature 421:499-506. 2003
  80. pmc Autophagy suppresses tumor progression by limiting chromosomal instability
    Robin Mathew
    University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
    Genes Dev 21:1367-81. 2007
    ..Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis...
  81. doi DNA repair pathways as targets for cancer therapy
    Thomas Helleday
    Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, off Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
    Nat Rev Cancer 8:193-204. 2008
    DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging ..
  82. ncbi Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest
    Valery Tarasov
    Molecular Oncology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D 82152 Martinsried, Germany
    Cell Cycle 6:1586-93. 2007
    ..Also expression of the primary miR-34a transcript was induced after p53 activation and by DNA damage in a p53-dependent manner...
  83. doi BRCA1 and BRCA2: different roles in a common pathway of genome protection
    Rohini Roy
    Molecular Biology Program and Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
    Nat Rev Cancer 12:68-78. 2012
    ..However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair...
  84. ncbi Human DNA repair genes
    R D Wood
    Imperial Cancer Research Fund, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts EN6 3LD, UK
    Science 291:1284-9. 2001
    ..Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process...
  85. ncbi Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
    Helen E Bryant
    The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
    Nature 434:913-7. 2005
    ..The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment...
  86. pmc Rewiring of genetic networks in response to DNA damage
    Sourav Bandyopadhyay
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    Science 330:1385-9. 2010
    ..in genetic interaction among yeast kinases, phosphatases, and transcription factors as the cell responds to DNA damage. Differential interactions uncover many gene functions that go undetected in static conditions...
  87. ncbi Negative control of p53 by Sir2alpha promotes cell survival under stress
    J Luo
    Institute of Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA
    Cell 107:137-48. 2001
    ..Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the ..
  88. ncbi Cellular senescence in aging primates
    Utz Herbig
    Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA
    Science 311:1257. 2006
    ..In addition, the same cells contain activated ataxia-telangiectasia mutated kinase and heterochromatinized nuclei, confirming their senescent status...
  89. pmc A base-excision DNA-repair protein finds intrahelical lesion bases by fast sliding in contact with DNA
    Paul C Blainey
    Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 103:5752-7. 2006
    ..5 kcal/mol (1 kcal = 4.2 kJ). This nearly barrierless Brownian sliding indicates that DNA glycosylases locate lesion bases by a massively redundant search in which the enzyme selectively binds 8-oxoguanine under kinetic control...
  90. ncbi Cell-cycle checkpoints and cancer
    Michael B Kastan
    Department of Hematology Oncology, St Jude Children s Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA
    Nature 432:316-23. 2004
    ..DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical ..
  91. ncbi DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
    S Y Shieh
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Cell 91:325-34. 1997
    ..Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, the oncoprotein MDM2, in vivo and ..
  92. ncbi A common mechanism of cellular death induced by bactericidal antibiotics
    Michael A Kohanski
    Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA
    Cell 130:797-810. 2007
    ..results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
  93. doi Transcription-coupled DNA repair: two decades of progress and surprises
    Philip C Hanawalt
    Department of Biology, Stanford University, 371 Serra Mall, Stanford, California 94305 5020, USA
    Nat Rev Mol Cell Biol 9:958-70. 2008
    Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA ..
  94. pmc Association of reactive oxygen species levels and radioresistance in cancer stem cells
    Maximilian Diehn
    Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA
    Nature 458:780-3. 2009
    ..with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs...
  95. doi CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines
    Amy M McCord
    Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA
    Clin Cancer Res 15:5145-53. 2009
    ..Therefore, to better understand the radioresponse of this cancer stem cell, we have used established cell lines as a framework for defining their in vitro radioresponse...
  96. pmc Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses
    Kai Rothkamm
    Fachrichtung Biophysik, Universitat des Saarlandes, 66421 Homburg, Germany
    Proc Natl Acad Sci U S A 100:5057-62. 2003
  97. ncbi Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
    Vassilis G Gorgoulis
    Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR 11527, Greece
    Nature 434:907-13. 2005
    b>DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive...
  98. ncbi TIGAR, a p53-inducible regulator of glycolysis and apoptosis
    Karim Bensaad
    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK
    Cell 126:107-20. 2006
    ..The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage...
  99. pmc A comprehensive catalogue of somatic mutations from a human cancer genome
    Erin D Pleasance
    Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
    Nature 463:191-6. 2010
    ..The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution ..
  100. pmc Balancing repair and tolerance of DNA damage caused by alkylating agents
    Dragony Fu
    Department of Biological Engineering, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Rev Cancer 12:104-20. 2012
    Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage...
  101. doi Living on a break: cellular senescence as a DNA-damage response
    Fabrizio d'Adda di Fagagna
    IFOM Foundation, FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy
    Nat Rev Cancer 8:512-22. 2008
    ..Common to both ageing and cancer is the generation of DNA damage and the engagement of the DNA-damage response pathways...

Research Grants74

  1. Variation in M. tuberculosis in response to host selection
    Sarah Fortune; Fiscal Year: 2009
    ..In these studies, we expect to provide fundamental insights into the mechanisms and targets of diversifying immune selection in M. tuberculosis. ..
  2. Chymase-Mediated MMP Activation in Ishemia Reperfusion Injury
    LOUIS JOSEPH DELL'ITALIA; Fiscal Year: 2013
    ..the dog in vivo results in a robust activation of intracellular MMPs within the cardiomyocyte nucleus along with DNA damage and loss of myosin...
  3. Optimization of DNA Repair by Abh8
    Lauren Endres; Fiscal Year: 2013
    ..These DNA lesions activate a multifaceted DNA damage response (DDR) to promote DNA repair by respective single and double strand break repair pathways (SSBR and DSBR)..
  4. Genome-wide recombination as a risk factor for nondisjunction
    NATASHA D HOLLIS; Fiscal Year: 2010
    ..the University of Alabama-Birmingham where her research examined the effect of ozone exposure on mitochondrial DNA damage and TNFa response in c57 mice...
  5. Role of SAMe on UBC9 and sumolyation in liver cancer and alcoholic liver injury
    Maria Lauda Tomasi; Fiscal Year: 2012
    ..of apoptotic pathways and by minimizing the acute cellular stress response associated with the accumulating DNA damage of tumor progression. Whether UBC9 is deregulated in hepatocellular carcinoma (HCC) is unknown...
  6. Retinoid and Carotenoid Depletion in Patients at High-Risk for Liver Cancer
    Peter H Gann; Fiscal Year: 2010
    ..in liver tissue and relate that to biomarkers of oxidative stress and pre-neoplastic change (hyperproliferation, DNA damage, nuclear aberration) in liver tissue...
  7. DNA Damage and Response in the Bladder Microenvironment.
    Bradley P Dixon; Fiscal Year: 2013
    ..microenvironment, and we have recently shown that this hyperosmolal stress disrupts gastrointestinal cell DNA damage signaling and repair...
  8. Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
    Mark M Huycke; Fiscal Year: 2012
    ..The bystander effect refers to collateral DNA damage in neighboring cells from activated cells that produce clastogens (or chromosome breaking factors)...
  9. Translational Machinery in Stress Signaling and Tumor Suppression
    THOMAS J contact BEGLEY; Fiscal Year: 2010
    ..In general, adaptation to stress promotes the repair of protein and DNA damage and must occur rapidly...
  10. Investigating Mechanism of Intracellular Rotational Transport with Optical T
    Jeffrey N Anker; Fiscal Year: 2012
    ..of secondary messengers and the depletion of antioxidants, cause global cytoskeletal damage and dysfunction, DNA damage, and cell death...
  11. Group A Streptococcus responses to oxidative stress
    Ioannis Gryllos; Fiscal Year: 2010
    ..Of these, polA.1 encodes DNA polymerase I, which has been implicated in DNA damage repair in several bacterial species, as well as in virulence of Salmonella typhimurium...
  12. Prostate cancer chemoprevention by penta-galloyl-glucose
    Junxuan Lu; Fiscal Year: 2013
    ..determine how PGG inhibits DNA replicative synthesis and the role in S-arrest and apoptosis with an emphasis on DNA damage/replicative stress-checkpoint pathways (e.g., ATM/ATR, p53). Aim 2...
  13. Comparison of Diesel and Biodiesel Emissions and Health Effects in Underground Mi
    Jefferey L Burgess; Fiscal Year: 2013
    ..Urinary 8- hydroxy-2'-deoxyguanosine (8-OHdG) will be assayed to assess oxidative DNA damage. Exhaled nitric oxide (NO), a marker of airway inflammation, and exhaled carbon monoxide (CO), a marker of CO ..
  14. Role of Diabetes in Development of Renal Cell Carcinoma
    SAMY LEWIZ HABIB; Fiscal Year: 2013
    ..Diabetes and hyperglycemia are associated with enhanced production of reactive oxygen species and induce DNA damage by several mechanisms...
  15. Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
    Xianglin Shi; Fiscal Year: 2013
    ..We will investigate the effects of C3G on UVB-induced lipid peroxidation, protein oxidation, and oxidative DNA damage in KSH mice...
  16. Molecular Mechanisms of Parvovirus Gene Expression and Replication
    Jianming Qiu; Fiscal Year: 2013
    ..Importantly, B19V infection induces a DNA damage response (DDR). Activation of ATR and DNA-PKcs facilitates viral DNA replication...
  17. Molecular mechanisms of lung disease in ataxia telangiectasia
    JoAnn M Sekiguchi; Fiscal Year: 2013
    ..phenotypes observed in A-T patients, including ILD, are hypothesized to result from defective responses to DNA damage and/or the consequences of accumulated oxidative damage in mutant cells...
  18. Weight Loss &Exercise Effects on Telomere Length in Postmenopausal Women
    ANNE M MCTIERNAN; Fiscal Year: 2012
    ..investigating associations between telomere length and other analytes already measured in the trial: DNA damage repair (COMET), sex hormones, insulin &glucose, inflammation (C-reactive protein, serum amyloid A, ..
  19. Bioassay for Breast Cancer Prevention
    JoEllen Welsh; Fiscal Year: 2010
    ..the role of genomic stability in dietary prevention of cancer and to develop an intermediate bioassay of DNA damage for testing efficacy of dietary agents...
  20. Environmental Risk Factors for Copy Number Variation in Human Chromosomes
    THOMAS EDWARD WILSON; Fiscal Year: 2010
    ..and those in cancers arise via mechanisms coupled to aberrant DNA replication and/or non-homologous repair of DNA damage. This suggests an unexpected mitotic, rather than meiotic, cell origin for many CNVs and has a number of ..
    Howard B Lieberman; Fiscal Year: 2013
    ..indicate that this evolutionarily conserved gene has multiple functions needed for the cellular response to DNA damage, including cell cycle checkpoints, DNA repair and pro-apoptotic activities...
  22. Interplay Between Tissue Architecture and Nuclear Organization in the DNA Damage
    Pierre Alexandre Vidi; Fiscal Year: 2013
    ..Cells have evolved elaborate DNA damage response (DDR) mechanisms to sense DSBs, activate repair pathways, and control cell cycle progression to prevent ..
  23. Role of Retroelements in Environmental Atherogenesis
    Kenneth S Ramos; Fiscal Year: 2010
    ..mechanisms responsible for BaP atherogenesis involve transcriptional deregulation of gene expression and DNA damage. Of interest are responses involving activation of the c-Ha-ras gene and long interspersed nuclear elements (..
    Gerd P Pfeifer; Fiscal Year: 2013
    ..that DNA methylation changes can be induced by endogenous mechanisms including inflammation and oxidative DNA damage. We will investigate inflammation-induced DNA methylation changes using a mouse model in which inflammation is ..
  25. UV-induced and NOS-mediated Zn elevation, translation regulation and apoptosis
    Shiyong Wu; Fiscal Year: 2012
    ..While most studies have focused on DNA damage-inducible, p53-dependent pathways of UV-induced apoptosis, membrane receptor mediated signaling pathways also ..
  26. Mechanisms of Stem Cell Self-Renewal and Aging
    PAUL CHRISTIAN SCHILLER; Fiscal Year: 2013
    ..is characterized by increased levels of reactive oxygen species (ROS) leading to oxidative stress and DNA damage. ROS appears to contribute to decreased osteoblastogenesis and bone mass as well as quality...
    Stephen J Lippard; Fiscal Year: 2013
    ..in this process are cancer cell entry, activation to form reactive species, DNA binding in the nucleus, and DNA damage-processing events...
  28. DNA Damage Checkpoint and Cancer
    Toru Ouchi; Fiscal Year: 2012
    ..of this project are to understand, in molecular terms, how signaling networks regulate the cellular response to DNA damage. Cellular DNA must be accurately replicated and transmitted to each daughter cell during cell division...
  29. Molecular Epidemiology of DNA Repair in Head and Neck Cancer
    Qingyi Wei; Fiscal Year: 2012
    ..Tobacco carcinogens cause a variety of DNA damage in the target cells, which may lead to uncontrolled cell growth, but the cells evolve to have the mechanism of ..
  30. DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
    R Stephen Lloyd; Fiscal Year: 2013
    ..These data will be correlated with rates of pathological changes and mitochondrial and nuclear DNA damage accumulation as measured by GC/MS and quantitative PCR...
  31. Role of beta-endorphin in cancer therapy induced fatigue
    David E Fisher; Fiscal Year: 2013
    ..Since control of this pathway is exerted by p53 (DNA damage sensor), we tested whether non-UV DNA damage triggers, especially ionizing radiation or certain ..
  32. The PKCepsilon-regulated oncogenic and tumor suppressor roles of ATF2 in melanoma
    ERIC KIRK LAU; Fiscal Year: 2013
    ..Specifically how PKCepsilon phosphorylation affects the transcriptional and non-transcriptional DNA damage response functions of ATF2 is not known...
  33. The Role of MYST Histone Acetyltransferase in Genome Stability
    M Mitchell Smith; Fiscal Year: 2013
    ..We will characterize DNA replication licensing, S phase progression, DNA damage response, and protein occupancy at DNA replication origins to define the involvement of Myst2 is proliferation ..
  34. Mechanism(s) of Hepatocyte Transformation by the Hepatitis B Virus X Protein
    Ourania M Andrisani; Fiscal Year: 2013
    ..pX activates cellular mitogenic pathways, promotes DNA re-replication-induced DNA damage and activates Plk1...
  35. Role of ALDH7A1 in Ethanol-Induced Oxidative Damage
    CHAD NICHOLAS BROCKER; Fiscal Year: 2011
    ..These molecules bind to protein, DNA and other compounds within cells causing enzyme inactivation, DNA damage and impaired cellular homeostasis...
  36. Folate Status, Genomic Uracil, and the Balance of Base Excision Repair Activity
    Michael D Wyatt; Fiscal Year: 2011
    ..Base excision repair (BER) corrects DNA damage and is generally considered to be valuable, but when folate deficiency occurs, BER may unwittingly contribute to ..
  37. Hepatitis B virus replication and DDB1
    Betty L Slagle; Fiscal Year: 2013
    ..To determine whether HBV activates the DNA damage response (DDR) as part of its acute replication strategy, uninfected and HBV- infected human liver tissue from ..
  38. Enhancing radiation and cisplatin HNSCC cell killing by inhibiting mitochondrial
    Lynn Harrison; Fiscal Year: 2013
    ..genome can result in loss of functional mitochondria, an induction of oxidative stress and greater nuclear DNA damage. Both nuclear and mitochondrial DNA repair mechanisms exist, although less is known about mitochondrial repair...
  39. The function of ATM protein in the biology of the adult neuron CNS:
    Karl Herrup; Fiscal Year: 2013
    ..dramatic neurological deficiencies, and while some features of A-T can be explained by a faulty response to DNA damage, it is hard to fully account for the neurological aspects of the disease on this basis...
  40. 14th International Workshop on Ataxia-Telangiectasia and ATM
    Richard A Gatti; Fiscal Year: 2010
    ..on various aspects of A-T and related neurodegenerative diseases, as well as on the role of ATM in cancer, the DNA damage response, and in viral infections that involve DNA integration...
  41. Chromatin Modifications and Vulnerability to Glutamate Toxicity
    ALEXEI D KONDRATYEV; Fiscal Year: 2010
    ..At the same time, oxidative stress is a major cause of DNA damage, which is also a common component of neuronal injury...
  42. Parental age at birth and risk of adult-onset cancer in female offspring
    Yani Lu; Fiscal Year: 2013
    ..levels of circulating estrogens with advancing gestational age and higher chance of germ cell mutations and DNA damage from older fathers (but not older mothers) supports the possibility that advanced maternal age may increase the ..
  43. Exploratory Studies on the Anti-Breast Cancer Function of Bamboo Extract
    Jun Panee; Fiscal Year: 2010
    ..DESCRIPTION (provided by applicant): Breast cancer is the most prevalent cancer among women in the United States. DNA damage induced by chemical exposure and oxidative stress, as well as estrogenic regulation of mammary gland ..
  44. The role of LKB1 in the maintenance of genomic stability.
    Zhi Xiang Xu; Fiscal Year: 2013
    ..We found that LKB1 interacts with ATM, BRCA1, and other DNA damage response (DDR) proteins in vivo...
  45. Evaluating the role of histone H3K79 methylation states in DNA damage repair in S
    Jeffrey S Thompson; Fiscal Year: 2010
    ..To counter the deleterious effects of UV radiation and other mutagenic agents, cells possess an array of DNA damage response and repair systems...
  46. Muscle stem cell therapy in a mouse model of premature aging
    Johnny Huard; Fiscal Year: 2010
    ..homeostatic reserve with aging is controversial, there are several lines of evidence that implicate accumulated DNA damage as a major determinant in the progression of age-related pathology...
  47. Functional study of C53 protein as a novel regulator of checkpoint kinases
    Honglin Li; Fiscal Year: 2012
    Our long-term goal is to elucidate the roles of a novel protein C53 in regulation of cell cycle progression and DNA damage response, and to explore potential utilization of this novel protein as a novel therapeutic target...
  48. Novel Therapeutic Targets in Necrotizing Enterocolitis
    Peter J Giannone; Fiscal Year: 2012
    ..NO dysregulation can lead to reactive nitrogen species, leading to cellular protein oxidation and DNA damage. Poly(ADP-ribose) polymerase (PARP) is up-regulated in response to these changes and can lead to cellular ..
    Vincent W Yang; Fiscal Year: 2013
    ..these changes often result in perturbation of critical signaling pathways such as Wnt, Notch, TGF?, PI3K, and DNA damage response (DDR), which are fundamentally important in the control of colonic epithelial homeostasis...
    Michael J Smerdon; Fiscal Year: 2013
    ..PUBLIC HEALTH RELEVANCE: DNA damage is detrimental to all living cells and repair of these lesions in mammalian cells is a 'frontline defense&..
  51. Mechanisms of Splicing Regulation During Environmental Stress in Yeast
    Jaclyn C Greimann; Fiscal Year: 2012
    ..of splicing in response to environmental stress by examining additional cellular stress conditions, such as DNA damage. RNA undergoes many different processing steps, in addition to splicing, throughout gene expression...
    Zbigniew Darzynkiewicz; Fiscal Year: 2013
    ..These assays will find utility in studies of DNA damage, DNA repair, carcinogenesis/mutagenesis, apoptosis, and in identifying the mechanism of action of antitumor ..
  53. ATM Controls Genomic Stability in Pluripotent Stem Cells
    JASON MARK BECKTA; Fiscal Year: 2013
    ..ATM, a serine-threonine kinase, plays a major role in many intracellular signaling networks, such as the DNA damage response...
  54. NADPH oxidase-associated transition from Barrett's esophagus to adenocarcinoma
    Weibiao Cao; Fiscal Year: 2013
    ..patients may cause high levels of ROS, increased cell proliferation and decreased apoptosis, which may lead to DNA damage and increased mutations, contributing to the progression from BE to dysplasia and to EA...
  55. Inactivation of Hdac3 in the cause, prevention, and treatment of HCC
    Scott W Hiebert; Fiscal Year: 2013
    ..Surprisingly, the S phase DNA damage checkpoint was activated in the absence of Hdac3...
  56. Hepatocyte Nox proteins in the pathogenesis of hepatocellular carcinoma
    Jinah Choi; Fiscal Year: 2013
    ..and increases the generation of hydroxyl radical and peroxynitrite close to the cell nucleus, inflicting DNA damage that can be mutagenic in the development of cancer...
  57. Metnase, PIKK, and RPA Roles in DNA Damage and Replication Stress Responses
    Jac A Nickoloff; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): Most cancer patients receive radio- and/or chemotherapy that causes DNA damage, which blocks DNA replication...
  58. The role of SIRT1/FOXO4 pathway in podocyte apoptosis of diabetes mellitus
    PETER YENLUNG CHUANG; Fiscal Year: 2013
    ..Deacetylation of FOXO3 by SIRT1 enhances the expression of antioxidant enzymes and DNA damage repair genes, but decreases the expression of apoptosis genes...
  59. Novel therapies for Fanconi anemia
    DAVID A contact WILLIAMS; Fiscal Year: 2010
    ..This is likely related to the defects in FA NHEJ or HR and to recent reports of involvement of the p53 DNA damage response pathway in reprogramming...
  60. Arsenic co-carcinogenesis with UVR: nitrosation and oxidation of target proteins
    Ke Jian Liu; Fiscal Year: 2013
    ..we will test the iNOS and NOX dependence for the reported synergism between arsenic and ultraviolet radiation in DNA damage and skin tumorigenesis in vivo using genetic models...
  61. Regulation of the VDJ recombinase during genotoxic stress
    Karla K Rodgers; Fiscal Year: 2013
    ..This is a particularly risky step, as DSBs are the most genotoxic form of DNA damage. In accordance with this, many lymphomas and leukemias contain characteristic chromosomal translocations between ..
  62. Organismal Radioprotection Through Pharmacological Quiescence
    JOHN S CHANT; Fiscal Year: 2010
    ..As quiescent cells are resistant to IR, PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage post-TBI. This enhanced survival of HSPC in turn translates into markedly reduced acute hematologic toxicity...
  63. DNA Repair Capacity and Risk of Pre-malignant Lesion in Lung Epithelium
    Hua Zhao; Fiscal Year: 2009
    ..It is hypothesized that the genotoxicity of neutrophils, including induction of oxidative DNA damage through release of reactive oxygen species (ROS) and myeloperoxidase (MPO)-related metabolic activation of ..
  64. Cohort Study of Genetic Susceptibility to Cutaneous Malignant Melanoma
    Jiali Han; Fiscal Year: 2010
    DESCRIPTION (provided by applicant): Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma;however, epidemiologic data are limited due to a limited number of ..
  65. Role of Polo-like kinase (Plk-1) in Hepatitis B Virus-mediated Hepatocellular Car
    Ourania M Andrisani; Fiscal Year: 2010
    ..Our previous studies have found that in non-transformed hepatocytes, pX induces DNA re-replication, resulting in DNA damage and polyploidy. As a result, the replication stress kinase ATR is activated which is known to activate p53...
  66. Genetic and Biochemical Analysis of DNA Exchange in Helicobacter pylori
    MARION SHONN DORER; Fiscal Year: 2010
    ..My studies show that DNA damage alters transcription of at least 25% of the H...
  67. Biotransformation of Estrogens to Carcinogenic Quinoids
    JUDY BOLTON; Fiscal Year: 2005
    ..Furthermore, these o-quinones can alkylate DNA that may lead to genotoxicity. Our data also suggests that DNA damage may be potentiated by the presence of an estrogen receptor (ER). The specific aims are: 1...
  68. Prophylactic Use of Vitamin E for Prevention of Occupational PAH-Induced Damage
    Debbie Mustacich; Fiscal Year: 2009
    ..Thus, a-tocopherol's action in eliminating BP-induced DNA damage likely involves regulation of hepatic detoxification and biliary excretion...
  69. DNA Damage and Tobacco-Induced Lung Cancer
    ERIC MOON SHONG TANG; Fiscal Year: 2009
    Carcinogens generated in tobacco smoke (TS) are able to cause DNA damage and mutations that may initiate lung carcinogenesis...
  70. Regulation of histone genes upon replication arrest and DNA damage
    HYERYUN PAIK; Fiscal Year: 2007
    ..Yeast cells lacking histones are inviable, whereas histone gene repression during S-phase triggers spontaneous DNA damage and cell cycle arrest in human cells...
    PAUL DOETSCH; Fiscal Year: 1993
    The biological consequences of oxidative and radiation-induced DNA damage include cell death, mutation and neoplastic transformation...
  72. Study of a FACTp140-SSRP1-associated p53 Kinase
    Hua Lu; Fiscal Year: 2006
    ..specific cellular process that modifies the properties of the p53 protein and thus its functions in response to DNA damage caused by UV radiation or cisplatin treatment...
  73. Biology of CHK2 Kinase In Lung Cancer
    Weixin Wang; Fiscal Year: 2005
    ..In response to DNA damage agents, such as ionizing radiation, ultraviolet radiation and chemical compounds, a cellular mechanism is ..
    Ted Weinert; Fiscal Year: 2000
    DESCRIPTION: In eukaryotic cells, DNA damage causes arrest of the cell cycle to allow repair of this damage. A number of genes, termed "checkpoint" genes, required for this arrest have been identified in yeast and in other organisms...