Skip to main content

Advertisement

SpringerLink
Log in

Fanconi anemia: a disorder defective in the DNA damage response

  • Progress in Hematology
  • Fanconi anemia and mechanisms of the DNA damage response
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin–phosphorylation network called the “FA pathway” and cooperate with other proteins involved in DNA repair and cell cycle control to repair ICL lesions and to maintain genome stability. In this review, we summarize recent exciting discoveries that have expanded our view of the molecular mechanisms operating in DNA repair and DNA damage signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. D’Andrea AD. Susceptibility pathways in Fanconi’s anemia, breast, cancer. N Engl J Med. 2010;362:1909–19.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sasaki MS, Tonomura A. A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross-linking agents. Cancer Res. 1973;33:1829–36.

    CAS  PubMed  Google Scholar 

  3. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, Laghmani el H, Joenje H, McDonald N, de Winter JP, Wang W, West SC. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell. 2007;25:331–43.

    Article  CAS  PubMed  Google Scholar 

  4. Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, Ohta T, Yu DS, McHugh PJ, Hickson ID, Venkitaraman AR, Kurumizaka H, Takata M. A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair. Mol Cell. 2005;19:841–7.

    Article  CAS  PubMed  Google Scholar 

  5. Wilson JB, Yamamoto K, Marriott AS, Hussain S, Sung P, Hoatlin ME, Mathew CG, Takata M, Thompson LH, Kupfer GM, Jones NJ. FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. Oncogene. 2008;27:3641–52.

    Article  CAS  PubMed  Google Scholar 

  6. Horejsi Z, Collis SJ, Boulton SJ. FANCM-FAAP24 and HCLK2: roles in ATR signalling and the Fanconi anemia pathway. Cell Cycle. 2009;8:1133–7.

    Article  CAS  PubMed  Google Scholar 

  7. Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ. FANCM FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell. 2008;32:313–24.

    Article  CAS  PubMed  Google Scholar 

  8. Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37:958–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mosedale G, Niedzwiedz W, Alpi A, Perrina F, Pereira-Leal JB, Johnson M, Langevin F, Pace P, Patel KJ. The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway. Nat Struct Mol Biol. 2005;12:763–71.

    Article  CAS  PubMed  Google Scholar 

  10. Gari K, Decaillet C, Stasiak AZ, Stasiak A, Constantinou A. The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions, replication forks. Mol Cell. 2008;29:141–8.

    Article  CAS  PubMed  Google Scholar 

  11. Singh TR, Saro D, Ali AM, Zheng XF, Du CH, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR. MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol Cell. 2010;37:879–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy PA, Shen X, Oostra AB, Du H, Steltenpool J, Lin T, Schuster B, Decaillet C, Stasiak A, Stasiak AZ, Stone S, Hoatlin ME, Schindler D, Woodcock CL, Joenje H, Sen R, de Winter JP, Li L, Seidman MM, Whitby MC, Myung K, Constantinou A, Wang W. A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol Cell. 2010;37:865–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schwab RA, Blackford AN, Niedzwiedz W. ATR activation, replication fork restart are defective in FANCM-deficient cells. EMBO J. 2010;29:806–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Luke-Glaser S, Luke B, Grossi S, Constantinou A. FANCM regulates DNA chain elongation, is stabilized by S-phase checkpoint signalling. EMBO J. 2010;29:795–805.

    Article  CAS  PubMed  Google Scholar 

  15. Wang W. Emergence of a DNA-damage response network consisting of Fanconi anaemia, BRCA proteins. Nat Rev Genet. 2007;8:735–48.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D’Andrea AD. Interaction of the Fanconi anemia proteins, BRCA1 in a common pathway. Mol Cell. 2001;7:249–62.

    Article  CAS  PubMed  Google Scholar 

  17. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D’Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007;129:289–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, Fraternali F, Freund M, Hartmann L, Grimwade D, Roberts RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42:406–9.

    Article  CAS  PubMed  Google Scholar 

  19. Neveling K, Endt D, Hoehn H, Schindler D. Genotype-phenotype correlations in Fanconi anemia. Mutat Res. 2009;668:73–91.

    Article  CAS  PubMed  Google Scholar 

  20. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–29.

    Article  CAS  PubMed  Google Scholar 

  21. Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, Livingston DM. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci USA. 2004;101:2357–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang F, Fan Q, Ren K, Andreassen PR. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res. 2009;7:1110–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet. 2004;13:1241–8.

    Article  CAS  PubMed  Google Scholar 

  24. Wang X, Andreassen PR, D’Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004;24:5850–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ohashi A, Zdzienicka MZ, Chen J, Couch FJ. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem. 2005;280:14877–83.

    Article  CAS  PubMed  Google Scholar 

  26. Kitao H, Yamamoto K, Matsushita N, Ohzeki M, Ishiai M, Takata M. Functional interplay between BRCA2/FancD1 and FancC in DNA repair. J Biol Chem. 2006;281:21312–20.

    Article  CAS  PubMed  Google Scholar 

  27. Zhi G, Wilson JB, Chen X, Krause DS, Xiao Y, Jones NJ, Kupfer GM, Fanconi anemia complementation group. FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction. Cancer Res. 2009;69:8775–83.

    Article  CAS  PubMed  Google Scholar 

  28. Hussain S, Witt E, Huber PA, Medhurst AL, Ashworth A, Mathew CG. Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1. Hum Mol Genet. 2003;12:2503–10.

    Article  CAS  PubMed  Google Scholar 

  29. Takata M, Ishiai M, Kitao H. The Fanconi anemia pathway: insights from somatic cell genetics using DT40 cell line. Mutat Res. 2009;668:92–102.

    Article  CAS  PubMed  Google Scholar 

  30. Raschle M, Knipscheer P, Enoiu M, Angelov T, Sun J, Griffith JD, Ellenberger TE, Scharer OD, Walter JC. Mechanism of replication-coupled DNA interstrand crosslink repair. Cell. 2008;134:969–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Minko IG, Harbut MB, Kozekov ID, Kozekova A, Jakobs PM, Olson SB, Moses RE, Harris TM, Rizzo CJ, Lloyd RS. Role for DNA polymerase kappa in the processing of N2–N2-guanine interstrand cross-links. J Biol Chem. 2008;283:17075–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Knipscheer P, Raschle M, Smogorzewska A, Enoiu M, Ho TV, Scharer OD, Elledge SJ, Walter JC. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science. 2009;326:1698–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge SJ. A genetic screen identifies FAN1 a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010;39:36–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kratz K, Schopf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavo E, Sartori AA, Hengartner MO, Jiricny J. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010;142:77–88.

    Article  CAS  PubMed  Google Scholar 

  36. MacKay C, Declais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010;142:65–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pace P, Mosedale G, Hodskinson MR, Rosado IV, Sivasubramaniam M, Patel KJ. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science. 2010;329:219–23.

    Article  CAS  PubMed  Google Scholar 

  38. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol. 2008;15:1138–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Andreassen PR, D’Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18:1958–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang LC, Stone S, Hoatlin ME, Gautier J. Fanconi anemia proteins stabilize replication forks. DNA Repair (Amst). 2008;7:1973–81.

    Article  CAS  Google Scholar 

  41. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316:1160–6.

    Article  CAS  PubMed  Google Scholar 

  42. Ho GP, Margossian S, Taniguchi T, D’Andrea AD. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol. 2006;26:7005–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pichierri P, Rosselli F. Fanconi anemia proteins, the s phase checkpoint. Cell Cycle. 2004;3:698–700.

    Article  CAS  PubMed  Google Scholar 

  44. Huang M, Kim JM, Shiotani B, Yang K, Zou L, D’Andrea AD. The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Mol Cell. 2010;39:259–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gong Z, Kim JE, Leung CC, Glover JN, Chen J. BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell. 2010;37:438–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nussenzweig A, Nussenzweig MC. Origin of chromosomal translocations in lymphoid cancer. Cell. 2010;141:27–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mirchandani KD, D’Andrea AD. The Fanconi anemia/BRCA pathway: a coordinator of cross-link repair. Exp Cell Res. 2006;312:2647–53.

    Article  CAS  PubMed  Google Scholar 

  48. Bunting SF, Nussenzweig A. Dangerous liaisons: Fanconi anemia and toxic nonhomologous end joining in DNA crosslink repair. Mol Cell. 2010;39:164–6.

    Article  CAS  PubMed  Google Scholar 

  49. Adamo A, Collis SJ, Adelman CA, Silva N, Horejsi Z, Ward JD, Martinez-Perez E, Boulton SJ, La Volpe A. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol Cell. 2010;39:25–35.

    Article  CAS  PubMed  Google Scholar 

  50. Houghtaling S, Newell A, Akkari Y, Taniguchi T, Olson S, Grompe M. Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining. Hum Mol Genet. 2005;14:3027–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Masao S. Sasaki (Professor-Emeritus, Kyoto University) for providing pictures in Fig. 1, Dr. James Alan Hejna (Graduate School of Biostudies, Kyoto University) for critical reading of this manuscript and useful suggestions, and our coworkers for discussions and help. The authors’ work has been supported by Grants-in aid from the Ministry of Education, Science, Sports, and Culture of Japan. The Uehara Memorial Foundation and Takeda foundation also provided financial support.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hiroyuki Kitao

  2. Laboratory of DNA damage signaling, Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Minoru Takata

Authors
  1. Hiroyuki Kitao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minoru Takata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minoru Takata.

About this article

Cite this article

Kitao, H., Takata, M. Fanconi anemia: a disorder defective in the DNA damage response. Int J Hematol 93, 417–424 (2011). https://doi.org/10.1007/s12185-011-0777-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0777-z

Keywords

Search

Navigation