fanconi anemia complementation group d2 protein

Summary

Summary: A Fanconi anemia complementation group protein that undergoes mono-ubiquitination by FANCL PROTEIN in response to DNA DAMAGE. Also, in response to IONIZING RADIATION it can undergo PHOSPHORYLATION by ataxia telangiectasia mutated protein. Modified FANCD2 interacts with BRCA2 PROTEIN in a stable complex with CHROMATIN, and it is involved in DNA REPAIR by homologous RECOMBINATION.

Top Publications

  1. Boichuk S, Hu L, Hein J, Gjoerup O. Multiple DNA damage signaling and repair pathways deregulated by simian virus 40 large T antigen. J Virol. 2010;84:8007-20 pubmed publisher
    ..Taken together, the interplay of LT with the DDR is more complex than anticipated, with individual domains of LT being connected to different subcomponents of the DDR and repair machinery...
  2. Zhang J, Zhao D, Wang H, Lin C, Fei P. FANCD2 monoubiquitination provides a link between the HHR6 and FA-BRCA pathways. Cell Cycle. 2008;7:407-13 pubmed
    ..Thus, these results provide further insights into the regulation of FANCD2 monoubiquitination as well as indicate a common link between the FA-BRCA and HHR6 pathways in the maintenance of genome integrity. ..
  3. Bae J, Mukhopadhyay S, Liu L, Zhang N, Tan J, Akhter S, et al. Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. Oncogene. 2008;27:5045-56 pubmed publisher
    ..In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein. ..
  4. Machida Y, Machida Y, Chen Y, Gurtan A, Kupfer G, D Andrea A, et al. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell. 2006;23:589-96 pubmed
    ..Therefore, UBE2T is the E2 in the Fanconi anemia pathway and has a self-inactivation mechanism that could be important for negative regulation of the Fanconi anemia pathway. ..
  5. Bhagwat N, Olsen A, Wang A, Hanada K, Stuckert P, Kanaar R, et al. XPF-ERCC1 participates in the Fanconi anemia pathway of cross-link repair. Mol Cell Biol. 2009;29:6427-37 pubmed publisher
    ..These data demonstrate that the unhooking of an ICL by XPF-ERCC1 is necessary for the stable localization of FANCD2 to the chromatin and subsequent homologous recombination-mediated DSB repair. ..
  6. Song I, Barkley L, Day T, Weiss R, Vaziri C. A novel role for Fanconi anemia (FA) pathway effector protein FANCD2 in cell cycle progression of untransformed primary human cells. Cell Cycle. 2010;9:2375-88 pubmed
    ..Taken together, our results suggest a novel role for the FA pathway in regulation of DNA synthesis and cell cycle progression. Inefficient DNA replication may contribute to the genome instability and cancer-propensity of FA patients. ..
  7. Meetei A, Medhurst A, Ling C, Xue Y, Singh T, Bier P, et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37:958-63 pubmed
    ..Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA. ..
  8. Yamamoto K, Hirano S, Ishiai M, Morishima K, Kitao H, Namikoshi K, et al. Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and DNA repair through a mechanism related to homologous recombination. Mol Cell Biol. 2005;25:34-43 pubmed
    ..Thus, we propose that FancD2 promotes a subpathway of HR that normally mediates gene conversion by a mechanism that avoids crossing over and hence SCEs. ..
  9. Niedzwiedz W, Mosedale G, Johnson M, Ong C, Pace P, Patel K. The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell. 2004;15:607-20 pubmed
    ..These studies reveal that the FA proteins cooperate with key mutagenesis and repair processes that enable replication of damaged DNA. ..

More Information

Publications62

  1. Hodson C, Cole A, Lewis L, Miles J, Purkiss A, Walden H. Structural analysis of human FANCL, the E3 ligase in the Fanconi anemia pathway. J Biol Chem. 2011;286:32628-37 pubmed publisher
    ..In addition, we characterize the binding of human FANCL with its partners, Ube2t, FANCD2, and FANCI. Mutational analysis reveals which residues are required for substrate binding, and we also show the domain required for E2 binding. ..
  2. Hussain S, Wilson J, Medhurst A, Hejna J, Witt E, Ananth S, et al. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet. 2004;13:1241-8 pubmed
    ..These findings suggest that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion. ..
  3. Nijman S, Huang T, Dirac A, Brummelkamp T, Kerkhoven R, D Andrea A, et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005;17:331-9 pubmed
    ..We propose that USP1 deubiquitinates FANCD2 when cells exit S phase or recommence cycling after a DNA damage insult and may play a critical role in the FA pathway by recycling FANCD2. ..
  4. Spardy N, Duensing A, Charles D, Haines N, Nakahara T, Lambert P, et al. The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells. J Virol. 2007;81:13265-70 pubmed
  5. Park H, Wang H, Zhang J, Datta S, Fei P. Convergence of Rad6/Rad18 and Fanconi anemia tumor suppressor pathways upon DNA damage. PLoS ONE. 2010;5:e13313 pubmed publisher
  6. Parmar K, Kim J, Sykes S, Shimamura A, Stuckert P, Zhu K, et al. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010;28:1186-95 pubmed publisher
    ..Collectively, our data reveal novel functions of Fancd2 and Usp1 in maintaining the bone marrow HSC compartment and suggest that FA pathway disruption may account for bone marrow failure in FA patients. ..
  7. Adamo A, Collis S, Adelman C, Silva N, Horejsi Z, Ward J, et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol Cell. 2010;39:25-35 pubmed publisher
    ..We propose that a critical function of the FA pathway is to channel lesions into accurate, as opposed to error-prone, repair pathways. ..
  8. Gordon S, Buchwald M. Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems. Blood. 2003;102:136-41 pubmed
    ..Direct interaction between FANCE and FANCD2 was also demonstrated in the yeast 2-hybrid system. This interaction involving an amino-terminal region of FANCD2 may provide a link between the FA protein complex and its downstream targets. ..
  9. Ho G, Margossian S, Taniguchi T, D Andrea A. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol. 2006;26:7005-15 pubmed
    ..These findings further support the functional connection of ATM/ATR kinases and FANCD2 in the DNA damage response and support a role for the FA pathway in the coordination of the S phase of the cell cycle. ..
  10. Chan K, Palmai Pallag T, Ying S, Hickson I. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol. 2009;11:753-60 pubmed publisher
    ..Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis. ..
  11. Yuan F, El Hokayem J, Zhou W, Zhang Y. FANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures. J Biol Chem. 2009;284:24443-52 pubmed publisher
    ..Our data suggest that the FANCI-FANCD2 complex may participate in repair of damaged replication forks through its preferential recognition of branched structures. ..
  12. Landais I, Sobeck A, Stone S, LaChapelle A, Hoatlin M. A novel cell-free screen identifies a potent inhibitor of the Fanconi anemia pathway. Int J Cancer. 2009;124:783-92 pubmed publisher
  13. Kalb R, Neveling K, Hoehn H, Schneider H, Linka Y, Batish S, et al. Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Am J Hum Genet. 2007;80:895-910 pubmed
    ..Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA. ..
  14. Alpi A, Patel K. Monoubiquitylation in the Fanconi anemia DNA damage response pathway. DNA Repair (Amst). 2009;8:430-5 pubmed publisher
    ..As this part of the FA pathway is still far from fully understood, we raise several points that must be addressed in future studies. ..
  15. Naim V, Rosselli F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol. 2009;11:761-8 pubmed publisher
    ..We reveal new crosstalk between FANC and BLM proteins, extending their interaction beyond the S-phase rescue of damaged DNA to the safeguarding of chromosome stability during mitosis. ..
  16. Pejovic T, Yates J, Liu H, Hays L, Akkari Y, Torimaru Y, et al. Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. Cancer Res. 2006;66:9017-25 pubmed
    ..Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer. ..
  17. Barroso E, Milne R, Fernandez L, Zamora P, Arias J, Benitez J, et al. FANCD2 associated with sporadic breast cancer risk. Carcinogenesis. 2006;27:1930-7 pubmed
    ..Our data indicate that a relationship between FANCD2 and sporadic breast cancer risk may exist. ..
  18. Tumini E, Plevani P, Muzi Falconi M, Marini F. Physical and functional crosstalk between Fanconi anemia core components and the GINS replication complex. DNA Repair (Amst). 2011;10:149-58 pubmed publisher
    ..However, depletion of PSF2 is not sufficient to reduce monoubiquitylation of FANCD2 or its localization to nuclear foci following DNA damage. Our results suggest a novel crosstalk between DNA replication and the FA pathway. ..
  19. Kratz K, Schöpf B, Kaden S, Sendoel A, Eberhard R, Lademann C, et al. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010;142:77-88 pubmed publisher
    ..The link of KIAA1018 to the FA pathway is further strengthened by its recruitment to DNA damage through interaction of its UBZ domain with monoubiquitylated FANCD2. We therefore propose to name KIAA1018 FANCD2-associated nuclease, FAN1. ..
  20. Tafel A, Wu L, McHugh P. Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures. J Biol Chem. 2011;286:15832-40 pubmed publisher
    ..Together, our results suggest that one role for HEL308 at sites of blocked replication might be to open up the parental strands to facilitate the loading of subsequent factors required for replication restart. ..
  21. Karanja K, Cox S, Duxin J, Stewart S, Campbell J. DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network. Cell Cycle. 2012;11:3983-96 pubmed publisher
    ..This is the first demonstration of the redundancy of human resection nucleases in the HDR step in replication-coupled repair, and suggests that DNA2 may represent a new mediator of the interplay between HDR and the FA/BRCA pathway. ..
  22. Long D, R schle M, Joukov V, Walter J. Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science. 2011;333:84-7 pubmed publisher
    ..Our results elucidate the functional link between the Fanconi anemia pathway and the recombination machinery during ICL repair. In addition, they demonstrate the complete repair of a DSB via homologous recombination in vitro...
  23. Pace P, Mosedale G, Hodskinson M, Rosado I, Sivasubramaniam M, Patel K. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science. 2010;329:219-23 pubmed publisher
    ..These results reveal a function for the FA pathway in processing DNA ends, thereby diverting double-strand break repair away from abortive NHEJ and toward homologous recombination. ..
  24. Jacquemont C, Taniguchi T. Proteasome function is required for DNA damage response and fanconi anemia pathway activation. Cancer Res. 2007;67:7395-405 pubmed
    ..The dependence of specific DNA damage-signaling steps on the proteasome may explain the sensitization of tumor cells to DNA-damaging chemotherapeutic agents by proteasome inhibitors. ..
  25. Folias A, Matkovic M, Bruun D, Reid S, Hejna J, Grompe M, et al. BRCA1 interacts directly with the Fanconi anemia protein FANCA. Hum Mol Genet. 2002;11:2591-7 pubmed
    ..The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting. The demonstrated interaction directly connects BRCA1 to the FA pathway of DNA repair. ..
  26. Hölzel M, van Diest P, Bier P, Wallisch M, Hoatlin M, Joenje H, et al. FANCD2 protein is expressed in proliferating cells of human tissues that are cancer-prone in Fanconi anaemia. J Pathol. 2003;201:198-203 pubmed
    ..FANCD2 expression is frequently expressed in proliferating cells as demonstrated by Ki-67 immunofluorescence double staining, consistent with a function of FANCD2 in DNA replication. ..
  27. Park W, Margossian S, Horwitz A, Simons A, D Andrea A, Parvin J. Direct DNA binding activity of the Fanconi anemia D2 protein. J Biol Chem. 2005;280:23593-8 pubmed
    ..This finding of DNA binding is the first biochemical activity identified for this key protein in the Fanconi anemia pathway. ..
  28. Pichierri P, Franchitto A, Rosselli F. BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks. EMBO J. 2004;23:3154-63 pubmed
  29. Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom J, Pessina F, et al. ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res. 2012;72:1149-56 pubmed publisher
    ..Together, our findings identify ATR as the kinase responsible for activating the FA pathway of DNA repair. ..
  30. Wilson J, Johnson M, Stuckert A, Trueman K, May S, Bryant P, et al. The Chinese hamster FANCG/XRCC9 mutant NM3 fails to express the monoubiquitinated form of the FANCD2 protein, is hypersensitive to a range of DNA damaging agents and exhibits a normal level of spontaneous sister chromatid exchange. Carcinogenesis. 2001;22:1939-46 pubmed
    ..NM3 and other "FA-like" Chinese hamster mutants should provide an important resource for the study of these processes in mammalian cells. ..
  31. Castillo P, Bogliolo M, Surralles J. Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage. DNA Repair (Amst). 2011;10:518-25 pubmed publisher
    ..We conclude that the handling of DNA damage after H(2)O(2)-induced oxidative stress requires the coordinated action of FANCD2 and ATM...
  32. Liu T, Ghosal G, Yuan J, Chen J, Huang J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science. 2010;329:693-6 pubmed publisher
    ..Thus, the mono-ubiquitylated ID complex recruits the downstream repair protein FAN1 and facilitates the repair of DNA interstrand cross-links. ..
  33. Xue Y, Li Y, Guo R, Ling C, Wang W. FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair. Hum Mol Genet. 2008;17:1641-52 pubmed publisher
    ..These data are consistent with participation of FANCM and its associated FA core complex in the FA pathway at both signaling through monoubiquitination and the ensuing DNA repair. ..
  34. Andreassen P, D Andrea A, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18:1958-63 pubmed
  35. Levran O, Attwooll C, Henry R, Milton K, Neveling K, Rio P, et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005;37:931-3 pubmed
    ..Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1. ..
  36. Dorsman J, Levitus M, Rockx D, Rooimans M, Oostra A, Haitjema A, et al. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29:211-8 pubmed
    ..These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI, since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592. ..
  37. Yoshikiyo K, Kratz K, Hirota K, Nishihara K, Takata M, Kurumizaka H, et al. KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proc Natl Acad Sci U S A. 2010;107:21553-7 pubmed publisher
  38. Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, et al. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell. 2001;7:241-8 pubmed
    ..thaliana, C. elegans, and Drosophila. Retroviral transduction of the cloned FANCD2 cDNA into FA-D2 cells resulted in functional complementation of MMC sensitivity. ..
  39. Zhou W, Otto E, Cluckey A, Airik R, Hurd T, Chaki M, et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012;44:910-5 pubmed publisher
    ..Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD. ..
  40. Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H. DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic Acids Res. 2012;40:4553-61 pubmed publisher
    ..Therefore, DNA may be the unidentified factor required for proper FANCD2 monoubiquitylation. ..
  41. van der Groep P, Hoelzel M, Buerger H, Joenje H, de Winter J, van Diest P. Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer. Breast Cancer Res Treat. 2008;107:41-7 pubmed
    ..FANCD2 is of independent prognostic value in sporadic breast cancer. ..
  42. Zhu W, Dutta A. Activation of fanconi anemia pathway in cells with re-replicated DNA. Cell Cycle. 2006;5:2306-9 pubmed
    ..In addition, FANCD2 is required for recruitment of Rad51 to foci in rereplicated cells, so that the repair pathways activated after small degrees of rereplication are expected to be compromised in cells with mutations in the FA pathway. ..
  43. Bruun D, Folias A, Akkari Y, Cox Y, Olson S, Moses R. siRNA depletion of BRCA1, but not BRCA2, causes increased genome instability in Fanconi anemia cells. DNA Repair (Amst). 2003;2:1007-13 pubmed
    ..Thus, BRCA2 is epistatic to FA genes for ICL repair, but not for damage-induced modification of FANCD2 and may act downstream form FANCD2. ..
  44. Gordon S, Alon N, Buchwald M. FANCC, FANCE, and FANCD2 form a ternary complex essential to the integrity of the Fanconi anemia DNA damage response pathway. J Biol Chem. 2005;280:36118-25 pubmed
    ..Thus, FANCE is shown to be a key mediator of protein interactions both in the architecture of the FA protein complex and in the connection of complex components to the putative downstream targets of complex activity. ..
  45. Collis S, Barber L, Ward J, Martin J, Boulton S. C. elegans FANCD2 responds to replication stress and functions in interstrand cross-link repair. DNA Repair (Amst). 2006;5:1398-406 pubmed
  46. Seal S, Barfoot R, Jayatilake H, Smith P, Renwick A, Bascombe L, et al. Evaluation of Fanconi Anemia genes in familial breast cancer predisposition. Cancer Res. 2003;63:8596-9 pubmed
    ..The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition. ..
  47. Geng L, Huntoon C, Karnitz L. RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. J Cell Biol. 2010;191:249-57 pubmed publisher
    ..Collectively, these experiments identify RAD18-mediated PCNA monoubiquitination as a central hub for the mobilization of the FA pathway by promoting FANCL-mediated FANCD2 monoubiquitylation. ..
  48. Zhang Q, Marquez Loza L, Eaton L, Duncan A, Goldman D, Anur P, et al. Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol. Blood. 2010;116:5140-8 pubmed publisher
    ..We conclude that Fancd2(-/-) mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. ..
  49. Naim V, Rosselli F. The FANC pathway and mitosis: a replication legacy. Cell Cycle. 2009;8:2907-11 pubmed
    ..These findings open new directions in understanding the mechanisms of chromosome fragility and the role of FANC proteins in preserving genome stability. ..
  50. Ben Yehoyada M, Wang L, Kozekov I, Rizzo C, Gottesman M, Gautier J. Checkpoint signaling from a single DNA interstrand crosslink. Mol Cell. 2009;35:704-15 pubmed publisher
    ..Repair occurs by both origin-dependent and origin-independent mechanisms. Our data suggest that cell sensitivity to crosslinking agents results from both checkpoint and DNA repair defects. ..
  51. Levitus M, Joenje H, de Winter J. The Fanconi anemia pathway of genomic maintenance. Cell Oncol. 2006;28:3-29 pubmed
    ..Finally, the possible role for the FA pathway, in particular FANCF and FANCB, in the origin of sporadic cancer is discussed. ..
  52. Bogliolo M, Lyakhovich A, Callen E, Castella M, Cappelli E, Ramirez M, et al. Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability. EMBO J. 2007;26:1340-51 pubmed
    ..Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability. ..
  53. Sobeck A, Stone S, Costanzo V, de Graaf B, Reuter T, de Winter J, et al. Fanconi anemia proteins are required to prevent accumulation of replication-associated DNA double-strand breaks. Mol Cell Biol. 2006;26:425-37 pubmed