Genomes and Genes
ataxia telangiectasia mutated proteins
Summary: A group of PROTEIN-SERINE-THREONINE KINASES which activate critical signaling cascades in double strand breaks, APOPTOSIS, and GENOTOXIC STRESS such as ionizing ultraviolet A light, thereby acting as a DNA damage sensor. These proteins play a role in a wide range of signaling mechanisms in cell cycle control.
- Buisson R, Lawrence M, Benes C, Zou L. APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition. Cancer Res. 2017;77:4567-4578 pubmed publisher..Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567-78. Â©2017 AACR. ..
- Schultz L, Chehab N, Malikzay A, Halazonetis T. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol. 2000;151:1381-90 pubmed..Thus, the fast kinetics of 53BP1 focus formation after irradiation and the lack of dependency on ATM and NBS1 suggest that 53BP1 functions early in the cellular response to DNA DSBs. ..
- Darrah E, Stoltz K, Ledwith M, Tarakanova V. ATM supports gammaherpesvirus replication by attenuating type I interferon pathway. Virology. 2017;510:137-146 pubmed publisher..This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection. ..
- Zhou B, Elledge S. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408:433-9 pubmed..This pathway regulates known responses such as cell-cycle arrest and apoptosis (programmed cell death), and has recently been shown to control additional processes including direct activation of DNA repair networks. ..
- Perkhofer L, Schmitt A, Romero Carrasco M, Ihle M, Hampp S, Ruess D, et al. ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. Cancer Res. 2017;77:5576-5590 pubmed publisher..Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576-90. Â©2017 AACR. ..
- Tahara K, Takizawa M, Yamane A, Osaki Y, Ishizaki T, Mitsui T, et al. Overexpression of B-cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response. Cancer Sci. 2017;108:1556-1564 pubmed publisher..This phenotypic change could be reproduced by interleukin-6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells. ..
- Tomimatsu N, Mukherjee B, Harris J, Boffo F, Hardebeck M, Potts P, et al. DNA-damage-induced degradation of EXO1 exonuclease limits DNA end resection to ensure accurate DNA repair. J Biol Chem. 2017;292:10779-10790 pubmed publisher..These findings indicate that the coupling of EXO1 activation with its eventual degradation is a timing mechanism that limits the extent of DNA end resection for accurate DNA repair. ..
- Henríquez Hernández L, Valenciano A, Foro Arnalot P, Álvarez Cubero M, Cozar J, Suarez Novo J, et al. Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression. BMC Med Genet. 2014;15:143 pubmed publisher..57 (CI 95% 1.28 - 5.16)). Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer. ..
- Renault A, Mebirouk N, Cavaciuti E, Le Gal D, Lecarpentier J, d Enghien C, et al. Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families. Carcinogenesis. 2017;38:994-1003 pubmed publisher..TL measurement alone is not a good marker for predicting cancer risk in A-T families. ..
- Lilyquist J, Laduca H, Polley E, Davis B, Shimelis H, Hu C, et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017;147:375-380 pubmed publisher..The knowledge that some genes are not associated with OC can reduce concerns of women found to carry pathogenic alterations in those genes. ..
- Pilie P, Johnson A, Hanson K, Dayno M, Kapron A, Stoffel E, et al. Germline genetic variants in men with prostate cancer and one or more additional cancers. Cancer. 2017;123:3925-3932 pubmed publisher..Cancer 2017;123:3925-32. © 2017 American Cancer Society. ..
- Damiola F, Pertesi M, Oliver J, Le Calvez Kelm F, Voegele C, Young E, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res. 2014;16:R58 pubmed publisher..However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study. ..
- Goto G, Ogi H, Biswas H, Ghosh A, Tanaka S, Sugimoto K. Two separate pathways regulate protein stability of ATM/ATR-related protein kinases Mec1 and Tel1 in budding yeast. PLoS Genet. 2017;13:e1006873 pubmed publisher..Asa1 and Pih1 are required for proper DNA damage checkpoint signaling. Our findings provide a model in which two different Tel2 pathways promote protein stabilization of Mec1 and Tel1 in budding yeast. ..
- Knittel G, Rehkämper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, et al. Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 2017;8:153 pubmed publisher..Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition. ..
- Green A, Budagyan K, Hayer K, Reed M, Savani M, Wertheim G, et al. Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint. Cancer Res. 2017;77:4579-4588 pubmed publisher..i>Cancer Res; 77(17); 4579-88. Â©2017 AACR. ..
- Hendriks C, Hartkamp J, Wiezorek S, Steinkamp A, Rossetti G, Luscher B, et al. Sulfoximines as ATR inhibitors: Analogs of VE-821. Bioorg Med Chem Lett. 2017;27:2659-2662 pubmed publisher..Together our findings suggest that the sulfilimidoyl- and sulfoximidoyl-substituted analogs are efficient ATR inhibitors. ..
- Takagi M, Yoshida M, Nemoto Y, Tamaichi H, Tsuchida R, Seki M, et al. Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor. J Natl Cancer Inst. 2017;109: pubmed publisher..Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics. ..
- Spehalski E, Capper K, Smith C, Morgan M, Dinkelmann M, Buis J, et al. MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress. Cancer Res. 2017;77:5327-5338 pubmed publisher..More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327-38. Â©2017 AACR. ..
- Chen C, Ruiz Vega R, Vasudeva P, Espitia F, Krasieva T, de Feraudy S, et al. ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment. Cell Rep. 2017;18:2331-2342 pubmed publisher..Taken together, these studies identify a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth. ..
- ..These results identify new regulatory details of the DNA damage response and further explain the chemosensitizing effects of HSP90 inhibitors. ..
- Wang Y, SHARPLESS N, Chang S. p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses. J Clin Invest. 2013;123:4489-501 pubmed publisher..Our results provide experimental evidence that p16(INK4a) exerts protective functions in proliferative cells bearing dysfunctional telomeres. ..
- Nikkilä J, Kumar R, Campbell J, Brandsma I, Pemberton H, Wallberg F, et al. Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. Br J Cancer. 2017;117:113-123 pubmed publisher..Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells. ..
- Horvath B, Kourová H, Nagy S, Németh E, Magyar Z, Papdi C, et al. Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control. EMBO J. 2017;36:1261-1278 pubmed publisher..Thus, plant homologs and analogues of major mammalian tumour suppressor proteins form a regulatory network that coordinates cell proliferation with cell and genome integrity. ..
- Saldivar J, Cortez D, Cimprich K. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol. 2017;18:622-636 pubmed publisher..We focus on the activities of ATR in the control of cell cycle checkpoints, origin firing and replication fork stability, and on how proper regulation of these processes is crucial to ensure faithful duplication of a challenging genome. ..
- Torres T, Russo L, Santos A, Marques G, Magalhaes Y, Tabassum S, et al. Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways. Biochim Biophys Acta. 2017;1861:1879-1894 pubmed publisher..The radioresistance of tumor cells is effectively reduced by a combination of approaches through the inhibition of DUSPs. ..
- Chen H, Wang L, Wang W, Cheng C, Zhang Y, Zhou Y, et al. ELABELA and an ELABELA Fragment Protect against AKI. J Am Soc Nephrol. 2017;28:2694-2707 pubmed publisher..Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI. ..
- Inano S, Sato K, Katsuki Y, Kobayashi W, Tanaka H, Nakajima K, et al. RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination. Mol Cell. 2017;66:622-634.e8 pubmed publisher..Collectively, our data reveal a mechanism that facilitates timely removal of RPA and RAD51 from DNA damage sites, which is crucial for progression to the late-phase HR and suppression of the FA phenotype. ..
- Antonelli M, Strappazzon F, Arisi I, Brandi R, D Onofrio M, Sambucci M, et al. ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy. Oncotarget. 2017;8:21692-21709 pubmed publisher..We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype. ..
- Geißler A, Geißler M, Kottmann D, Lutz L, Fichter C, Fritsch R, et al. ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer. Oncotarget. 2017;8:17164-17190 pubmed publisher..Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy. ..
- Mombach J, Bugs C, Chaouiya C. Modelling the onset of senescence at the G1/S cell cycle checkpoint. BMC Genomics. 2014;15 Suppl 7:S7 pubmed publisher..This model qualitatively agrees with most experimental observations, including experiments involving mutations. Furthermore, it provides some predictions. ..
- Pettersson M, Viljakainen H, Loid P, Mustila T, Pekkinen M, Armenio M, et al. Copy Number Variants Are Enriched in Individuals With Early-Onset Obesity and Highlight Novel Pathogenic Pathways. J Clin Endocrinol Metab. 2017;102:3029-3039 pubmed publisher..The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity. ..
- Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, et al. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration. EMBO J. 2017;36:2161-2176 pubmed publisher..Our model shows how cell cycle restart can occur before completion of DNA repair and suggests a mechanism for checkpoint adaptation in human cells. ..
- Paulikova S, Petera J, Sirak I, Vosmik M, Drastíková M, Dusek L, et al. ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer. Neoplasma. 2014;61:70-6 pubmed..We conclude that haplotypes instead of single nucleotide polymorphic sites in the genes may better characterize the individual radiosensitivity. ..
- Holden J, Taylor E, Lindsay H. Cip29 is phosphorylated following activation of the DNA damage response in Xenopus egg extracts. PLoS ONE. 2017;12:e0181131 pubmed publisher..Taken together, these data identify Cip29 as a novel target of the DNA damage response and suggest that the damage-dependent modification of Cip29 may relate to a role in the regulation of gene expression after DNA damage. ..
- Ji S, Zhu L, Gao Y, Zhang X, Yan Y, Cen J, et al. Baf60b-mediated ATM-p53 activation blocks cell identity conversion by sensing chromatin opening. Cell Res. 2017;27:642-656 pubmed publisher..These findings shed light on cellular responses to lineage conversion by revealing a function of the ATM-p53 pathway in sensing chromatin opening. ..
- Kumar V, Fleming T, Terjung S, Gorzelanny C, Gebhardt C, Agrawal R, et al. Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. Nucleic Acids Res. 2017;45:10595-10613 pubmed publisher..Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis. ..
- Shiloh Y. ATM: from phenotype to functional genomics--and back. Ernst Schering Res Found Workshop. 2002;:51-70 pubmed
- Lu Y, Knapp M, Crawford K, Warne R, Elling R, Yan K, et al. Rationally Designed PI3K? Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors. J Mol Biol. 2017;429:1684-1704 pubmed publisher..The ability to obtain structural and binding data for these PI3K? mutants, together with their ATR-like inhibitor binding profiles, makes these chimeric PI3K? proteins valuable model systems for structure-based inhibitor design. ..
- Aird K, Zhang R. ATM in senescence. Oncotarget. 2015;6:14729-30 pubmed
- Palisoul M, Mullen M, Feldman R, Thaker P. Identification of molecular targets in vulvar cancers. Gynecol Oncol. 2017;146:305-313 pubmed publisher..05). Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options. ..
- Hollingworth R, Horniblow R, Forrest C, Stewart G, Grand R. Localization of Double-Strand Break Repair Proteins to Viral Replication Compartments following Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus. J Virol. 2017;91: pubmed publisher..Overall, this study extends our understanding of the virus-host interactions that occur during lytic replication of KSHV and provides a deeper insight into how the DDR is manipulated during viral infection. ..
- Lane S, Morgan S, Wu T, Collins J, Merriman J, Elinati E, et al. DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes. Development. 2017;144:3475-3486 pubmed publisher..Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores. ..
- Sinha N, Panda P, Naik P, Das D, Mukhopadhyay S, Maiti T, et al. Abrus agglutinin promotes irreparable DNA damage by triggering ROS generation followed by ATM-p73 mediated apoptosis in oral squamous cell carcinoma. Mol Carcinog. 2017;56:2400-2413 pubmed publisher..In conclusion, we established a connection among ROS, ATM and p73 in AGG-induced apoptosis, which might be useful in enhancing the therapeutic targeting of p53 deficient oral squamous cell carcinoma. ..
- Kemp M. DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH). J Biol Chem. 2017;292:12424-12435 pubmed publisher..Together, these results reveal a previously unknown role for transcription factor IIH in ATR kinase activation in non-replicating, non-cycling cells. ..
- Li C, Park S, Zhang X, Eisenberg L, Zhao H, Darzynkiewicz Z, et al. Nuclear Gene 33/Mig6 regulates the DNA damage response through an ATM serine/threonine kinase-dependent mechanism. J Biol Chem. 2017;292:16746-16759 pubmed publisher..On the basis of these findings and our previous studies, we propose that Gene 33 is a proximal regulator of DDR that promotes DNA repair. ..
- Chwastek J, Jantas D, LasoÅ„ W. [The role of ATM kinase in neurodegeneration]. Postepy Biochem. 2014;60:313-22 pubmed..The regulation of prosurvival processes which are controlled by ATM kinase, may prove an attractive therapeutic strategy in treatment of neurodegenerative diseases. ..
- Lavin M, Shiloh Y. The genetic defect in ataxia-telangiectasia. Annu Rev Immunol. 1997;15:177-202 pubmed..The mutations causing A-T completely inactivate or eliminate the ATM protein. This protein has been detected and localized to different subcellular compartments. ..
- Sarin N, Engel F, Kalayda G, Mannewitz M, Cinatl J, Rothweiler F, et al. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS ONE. 2017;12:e0181081 pubmed publisher..In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis. ..
- Lin X, Wei F, Major P, Al Nedawi K, Al Saleh H, Tang D. Microvesicles Contribute to the Bystander Effect of DNA Damage. Int J Mol Sci. 2017;18: pubmed publisher..Taken together, we provide evidence supporting that MVs are a source of the DNA damage-induced bystander effect. ..
- Yeom S, Kim S, Jeong H, Jang K. Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop. J Gen Virol. 2017;98:1774-1784 pubmed publisher..In conclusion, HBx modulates its own protein level via a negative feedback loop involving p53 and Siah-1 to control HBV propagation. ..
- Park M, Upton D, Blackmon M, Dixon V, Craver S, Neal D, et al. Anacardic acid inhibits pancreatic cancer cell growth, and potentiates chemotherapeutic effect by Chmp1A - ATM - p53 signaling pathway. BMC Complement Altern Med. 2018;18:71 pubmed publisher..Our data suggests that Anacardic Acid might be a promising complementary supplement to slow the initiation or progression of pancreatic cancer. ..
- Barazzuol L, Ju L, Jeggo P. A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLoS Biol. 2017;15:e2001264 pubmed publisher..Consequently, their repopulation occurs rapidly from irradiated progenitors rather than via qNSC activation. ..
- Kim J, Choi I, Lee Y. Involvement of Atm and Trp53 in neural cell loss due to Terf2 inactivation during mouse brain development. Histochem Cell Biol. 2017;148:489-501 pubmed publisher..These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis. ..
- Kuranova M, Pleskach N, Ledashcheva T, Mikhel son V, Spivak I. [Mosaic forms of ataxia-telangiectasia]. Tsitologiia. 2014;56:619-29 pubmed
- Agathanggelou A, Smith E, Davies N, Kwok M, Zlatanou A, Oldreive C, et al. USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status. Blood. 2017;130:156-166 pubmed publisher..Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised. ..
- Pennisi R, Antoccia A, Leone S, Ascenzi P, di Masi A. Hsp90Î± regulates ATM and NBN functions in sensing and repair of DNA double-strand breaks. FEBS J. 2017;284:2378-2395 pubmed publisher..Overall, present data shed light on the regulatory role of Hsp90Î± on the DDR, controlling ATM and NBN stability and influencing the DSBs signaling and repair. ..
- Bernstein J, Concannon P. ATM, radiation, and the risk of second primary breast cancer. Int J Radiat Biol. 2017;93:1121-1127 pubmed publisher..However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC)...
- Iwata T, Uchino T, Koyama A, Johmura Y, Koyama K, Saito T, et al. The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy. PLoS ONE. 2017;12:e0178221 pubmed publisher..Our results thus reveal that combination treatment of CBP-93872 with known chemotherapeutic agents inhibits phosphorylation of ATR and Chk1, and induces cell death. ..
- Paul A, Wang B. RNF8- and Ube2S-Dependent Ubiquitin Lysine 11-Linkage Modification in Response to DNA Damage. Mol Cell. 2017;66:458-472.e5 pubmed publisher..Thus, our study highlights the importance of linkage-specific ubiquitination at DNA damage sites, and it reveals that Lys11-linkage ubiquitin modification plays a crucial role in the DNA damage response. ..
- Suvorova I, Kozhukharova I, Nikol skiĭ N, Pospelov V. [ATM/ATR signaling pathway activation in human embryonic stem cells after DNA damage]. Tsitologiia. 2013;55:841-51 pubmed..However p53 activation and subsequent induction of p21 gene expression after DNA damage do not result in p21 protein accumulation due to proteasomal degradation. ..
- Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5: pubmed publisher..Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR. ..
- Darrah E, Kulinski J, Mboko W, Xin G, Malherbe L, Gauld S, et al. B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection. J Virol. 2017;91: pubmed publisher..Thus, our study defines a proviral role of B cell-specific ATM expression during chronic gammaherpesvirus infection. ..
- Feng Y, Xiang J, Liu S, Guo T, Yan G, Feng Y, et al. H2AX facilitates classical non-homologous end joining at the expense of limited nucleotide loss at repair junctions. Nucleic Acids Res. 2017;45:10614-10633 pubmed publisher..This may prevent outcomes such as non-repair and translocations, which are generally more destabilizing to genomes than short deletions and insertions from local NHEJ. ..
- Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999;283:1321-5 pubmed..Thus, in some cells, telomere shortening may signal cell death rather than senescence. ..