Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The Fanconi anaemia/BRCA pathway

Nature Reviews Cancer volume 3, pages 23–34 (2003)Cite this article

Key Points

  • Fanconi anaemia (FA) is an autosomal recessive disease that is characterized by developmental abnormalities, cancer susceptibility and cellular sensitivity to crosslinking agents.

  • The seven cloned FA proteins interact in a common pathway. Five FA proteins (A, C, E, F and G) regulate the activation, via monoubiquitylation, of FANCD2.

  • Activated FANCD2 is targeted to BRCA1 nuclear foci. The FANCD1 gene is BRCA2.

  • The FA/BRCA pathway seems to regulate DNA repair by homologous recombination.

  • Ionizing radiation activates the ATM-dependent phosphorylation of FANCD2, resulting in an intra-S checkpoint response.

  • FANCD2 interacts with the MRE11–NBS1–RAD50 complex in the repair of DNA crosslinks.

  • Somatic inactivation of the FA/BRCA pathway accounts for the chromosomal instability of some cancers in the general population.

  • Mouse models for FA subtypes A, C, D1, D2 and G have been generated.

  • DNA crosslink repair, which is defective in cells from FA patients, requires S-phase arrest and homologous recombination repair.

Abstract

Fanconi anaemia (FA) is a rare genetic cancer-susceptibility syndrome that is characterized by congenital abnormalities, bone-marrow failure and cellular sensitivity to DNA crosslinking agents. Seven FA-associated genes have recently been cloned, and their products were found to interact with well-known DNA-damage-response proteins, including BRCA1, ATM and NBS1. The FA proteins could therefore be involved in the cell-cycle checkpoint and DNA-repair pathways. Recent studies implicate the FA proteins in the process of repairing chromosome defects that occur during homologous recombination, and disruption of the FA genes results in chromosome instability — a common feature of many human cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Fanconi anaemia/BRCA pathway.
Figure 2: Interaction of the FA/BRCA pathway with the ATM kinase.
Figure 3: Interaction of the FA/BRCA pathway with the MRE11 complex (NBS–MRE11–RAD50).
Figure 4: Co-localization of the NBS1–MRE11–RAD50 complex with FANCD2 in DNA-damage-inducible subnuclear foci.

Similar content being viewed by others

References

  1. Grompe, M. & D'Andrea, A. Fanconi anemia and DNA repair. Hum. Mol. Genet. 10, 2253–2259 (2001).

    CAS  PubMed  Google Scholar 

  2. Joenje, H. & Patel, K. J. The emerging genetic and molecular basis of Fanconi anaemia. Nature Rev. Genet. 2, 446–457 (2001).

    CAS  PubMed  Google Scholar 

  3. Auerbach, A. D. Fanconi anemia. Dermatol. Clin. 13, 41–49 (1995).

    CAS  PubMed  Google Scholar 

  4. Alter, B. P. Fanconi's anemia and malignancies. Am. J. Hematol. 53, 99–110 (1996).

    CAS  PubMed  Google Scholar 

  5. Rosenberg, P. S., Greene, M. H. & Alter, B. P. Cancer incidence in persons with Fanconi's anemia. Blood 5 Sept 2002 (doi:10.1182/blood-2002-05–1498).

  6. D'Andrea, A. D. & Grompe, M. Molecular biology of Fanconi anemia: implications for diagnosis and therapy. Blood 90, 1725–1736 (1997).

    CAS  PubMed  Google Scholar 

  7. Kubbies, M., Schindler, D., Hoehn, H., Schinzel, A. & Rabinovitch, P. S. Endogenous blockage and delay of the chromosome cycle despite normal recruitment and growth phase explain poor proliferation and frequent edomitosis in Fanconi anemia cells. Am. J. Hum. Genet. 37, 1022–1030 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kaiser, T. N. et al. Flow cytometric characterization of the response of Fanconi's anemia cells to mitomycin C treatment. Cytometry 2, 291–297 (1982).

    CAS  PubMed  Google Scholar 

  9. Akkari, Y. M. et al. The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase. Mol. Genet. Metab. 74, 403–412 (2001).

    CAS  PubMed  Google Scholar 

  10. Auerbach, A. D. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp. Hematol. 21, 731–733 (1993).

    CAS  PubMed  Google Scholar 

  11. Waisfisz, Q. et al. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nature Genet. 22, 379–383 (1999).

    CAS  PubMed  Google Scholar 

  12. Pulsipher, M. et al. Subtyping analysis of Fanconi anemia by immunoblotting and retroviral gene transfer. Mol. Med. 4, 468–479 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hanenberg, H. et al. Phenotypic correction of primary Fanconi anemia T cells with retroviral vectors as a diagnostic tool. Exp. Hematol. 30, 410–420 (2002).

    CAS  PubMed  Google Scholar 

  14. Guinan, E. C., Lopez, K. D., Huhn, R. D., Felser, J. M. & Nathan, D. G. Evaluation of granulocyte–macrophage colony-stimulating factor for treatment of pancytopenia in children with fanconi anemia. J. Pediatr. 124, 144–150 (1994).

    CAS  PubMed  Google Scholar 

  15. Davies, S. M. et al. Unrelated donor bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant. 17, 43–47 (1996).

    CAS  PubMed  Google Scholar 

  16. Gluckman, E. et al. Transplantation of umbilical cord blood in Fanconi's anemia. Nouvelle Revue Francaise d Hematologie 32, 423–425 (1990).

    CAS  PubMed  Google Scholar 

  17. Wagner, J. E. Umbilical cord blood stem cell transplantation. Am. J. Pediatr. Hematol. Oncol. 15, 169–174 (1993).

    CAS  PubMed  Google Scholar 

  18. Yoshimasu, T. et al. Prompt and durable hematopoietic reconstitution by unrelated cord blood transplantation in a child with Fanconi anemia. Bone Marrow Transplant. 27, 767–769 (2001).

    CAS  PubMed  Google Scholar 

  19. Verlinsky, Y., Rechitsky, S., Schoolcraft, W., Strom, C. & Kuliev, A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 285, 3130–3133 (2001).

    CAS  PubMed  Google Scholar 

  20. Liu, J. M. et al. Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC). Hum. Gene Ther. 10, 2337–2346 (1999).

    CAS  PubMed  Google Scholar 

  21. Liu, J. M. et al. Retroviral mediated gene transfer of the Fanconi anemia complementation group C gene to hematopoietic progenitors of group C patients. Hum. Gene Ther. 8, 1715–1730 (1997).

    CAS  PubMed  Google Scholar 

  22. Strathdee, C. A., Gavish, H., Shannon, W. R. & Buchwald, M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature 356, 763–767 (1992). Describes the first successful cloning of a Fanconi anemia cDNA, by functional complementation of an FA-C lymphoblast line. A similar strategy was subsequently used for the cloning of the FANCA, FANCG, FANCF and FANCE cDNAs.

    CAS  PubMed  Google Scholar 

  23. Lo Ten Foe, J. R. et al. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nature Genet. 14, 320–323 (1996).

    CAS  PubMed  Google Scholar 

  24. de Winter, J. P. et al. Isolation of a cDNA representing the fanconi anemia complementation group E gene. Am. J. Hum. Genet. 67, 1306–1308 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. de Winter, J. P. et al. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nature Genet. 24, 15–16 (2000).

    CAS  PubMed  Google Scholar 

  26. de Winter, J. P. et al. The Fanconi anaemia group G gene FANCG is identical with XRCC9. Nature Genet. 20, 281–283 (1998).

    CAS  PubMed  Google Scholar 

  27. Positional cloning of the Fanconi anaemia group A gene. The Fanconi anaemia/breast cancer consortium. Nature Genet. 14, 324–328 (1996).

  28. Timmers, C. et al. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol. Cell 7, 241–248 (2001). Describes the position cloning of the Fanconi anaemia gene, FANCD2 . This paper also shows that the FANCD2 cDNA can functionally complement the mitomycin C sensitivity of FA-D2 cells.

    CAS  PubMed  Google Scholar 

  29. Whitney, M. A., Jakobs, P., Kaback, M., Moses, R. E. & Grompe, M. The Ashkenazi Jewish Fanconi anemia mutation: incidence among patients and carrier frequency in the at-risk population. Hum. Mutat. 3, 339–341 (1994).

    CAS  PubMed  Google Scholar 

  30. Verlander, P. C. et al. Carrier frequency of the IVS4 + 4 A→T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Blood 86, 4034–4038 (1995).

    CAS  PubMed  Google Scholar 

  31. Faivre, L. et al. Association of complementation group and mutation type with clinical outcome in fanconi anemia. Blood 96, 4064–4070 (2000).

    CAS  PubMed  Google Scholar 

  32. Gillio, A. P., Verlander, P. C., Batish, S. D., Giampietro, P. F. & Auerbach, A. D. Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study. Blood 90, 105–110 (1997).

    CAS  PubMed  Google Scholar 

  33. Liu, T. et al. Cloning and characterization of the zebrafish homologue of the Fanconi anemia protein, FANCD2. Blood 100, 43a (2002).

    Google Scholar 

  34. D'Andrea, A. D. Fanconi anaemia forges a novel pathway. Nature Genet. 14, 240–242 (1996).

    CAS  PubMed  Google Scholar 

  35. Carreau, M. & Buchwald, M. Fanconi's anemia: what have we learned from the genes so far? Mol. Med. Today 4, 201–206 (1998).

    CAS  PubMed  Google Scholar 

  36. Kupfer, G. M., Naf, D., Suliman, A., Pulsipher, M. & D'Andrea, A. D. The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Nature Genet. 17, 487–490 (1997).

    CAS  PubMed  Google Scholar 

  37. Garcia-Higuera, I., Kuang, Y., Naf, D., Wasik, J. & D'Andrea, A. D. Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex. Mol. Cell Biol. 19, 4866–4873 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamashita, T. et al. The Fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation. Proc. Natl Acad. Sci. USA 95, 13085–13090 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. de Winter, J. P. et al. The fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum. Mol. Genet. 9, 2665–2674 (2000). Shows that the FANCC, FANCG, FANCA and FANCF proteins accumulate as a complex in the nucleus of normal human cells, supporting the concept of an FA pathway.

    CAS  PubMed  Google Scholar 

  40. Medhurst, A. L., Huber, P. A., Waisfisz, Q., de Winter, J. P. & Mathew, C. G. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum. Mol. Genet. 10, 423–429 (2001).

    CAS  PubMed  Google Scholar 

  41. Garcia-Higuera, I., Kuang, Y., Denham, J. & D'Andrea, A. D. The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the fanconi anemia complex. Blood 96, 3224–3230 (2000).

    CAS  PubMed  Google Scholar 

  42. Qiao, F., Moss, A. & Kupfer, G. M. Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner. J. Biol. Chem. 276, 23391–23396 (2001).

    CAS  PubMed  Google Scholar 

  43. Pace, P. et al. FANCE: the link between Fanconi anaemia complex assembly and activity. EMBO J. 21, 3414–3423 (2002). Shows that the FANCE gene is a component of the FA complex, is required for the accumulation of FANCC in the nucleus, and provides a functional connection between the FA complex and FANCD2.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Nakanishi, K. et al. Functional analysis of patient-derived mutations in the Fanconi anemia gene, FANCG/XRCC9. Exp. Hematol. 29, 842–849 (2001).

    CAS  PubMed  Google Scholar 

  45. Garcia-Higuera, I. et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol. Cell 7, 249–262 (2001). Shows that six cloned FA proteins (A, C, D2, E, F and G) interact in a common pathway, resulting in the monoubiquitylation of FANCD2 and its targeting to BRCA1-containing nuclear foci.

    CAS  PubMed  Google Scholar 

  46. Taniguchi, T. et al. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 100, 2414–2420 (2002).

    CAS  PubMed  Google Scholar 

  47. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lorick, K. L. et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc. Natl Acad. Sci. USA 96, 11364–11369 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Patel, K. J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).

    CAS  PubMed  Google Scholar 

  50. Kraakman-van der Zwet, M. et al. Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions. Mol. Cell. Biol. 22, 669–679 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. McAllister, K. A. et al. Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res. 62, 990–994 (2002).

    CAS  PubMed  Google Scholar 

  52. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002). Shows that some rare FA patients have biallelic inactivation of the BRCA2 gene. Cells from FA-D1 cells can be functionally complemented with the BRCA2 gene.

    CAS  PubMed  Google Scholar 

  53. Digweed, M. et al. Attenuation of the formation of DNA-repair foci containing RAD51 in Fanconi anaemia. Carcinogenesis 23, 1121–1126 (2002).

    CAS  PubMed  Google Scholar 

  54. Folias, A. et al. BRCA1 interacts directly with the Fanconi anemia protein, FANCA. Hum. Mol. Genet. 11, 2591–2597 (2002).

    CAS  PubMed  Google Scholar 

  55. Margossian, S. et al. Regulated interaction of the Fanconi anemia protein, FANCD2, with damaged chromatin. Blood 100, 9a (2002).

    Google Scholar 

  56. D'Andrea, A. D. & Pellman, D. Deubiquitinating enzymes: a new class of biological regulators. Crit. Rev. Biochem. Mol. Biol. 33, 337–352 (1998).

    CAS  PubMed  Google Scholar 

  57. Gatti, R. A. The inherited basis of human radiosensitivity. Acta Oncol. 40, 702–711 (2001).

    CAS  PubMed  Google Scholar 

  58. Alter, B. P. Radiosensitivity in Fanconi's anemia patients. Radiother. Oncol. 62, 345–347 (2002).

    PubMed  Google Scholar 

  59. Khanna, K. et al. in DNA Damage and Repair (eds Nickoloff, J. A. & Hoekstra, M.) 395–442 (Humana Press, Totowa, New Jersey, 1999).

    Google Scholar 

  60. Banin, S. et al. Enhance phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674–1677 (1998).

    CAS  PubMed  Google Scholar 

  61. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).

    CAS  PubMed  Google Scholar 

  62. Lim, D. S. et al. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404, 613–617 (2000).

    CAS  PubMed  Google Scholar 

  63. Gatei, M. et al. ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. 25, 115–119 (2000).

    CAS  PubMed  Google Scholar 

  64. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    CAS  PubMed  Google Scholar 

  65. Taniguchi, T. et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109, 459–472 (2002). Shows that the FANCD2 protein undergoes two discrete post-translational modifications — an ATM-dependent phosphorylation and an FA-complex-dependent monoubiquitylation. Each modification activates a different cellular function.

    CAS  PubMed  Google Scholar 

  66. Xu, B., Kim, S. & Kastan, M. B. Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol. Cell. Biol. 21, 3445–3450 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shiloh, Y. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev. 11, 71–77 (2001).

    CAS  PubMed  Google Scholar 

  68. Carney, J. P. Chromosomal breakage syndromes. Curr. Opin. Immunol. 11, 443–447 (1999).

    CAS  PubMed  Google Scholar 

  69. Petrini, J. H. The Mre11 complex and ATM: collaborating to navigate S phase. Curr. Opin. Cell Biol. 12, 293–296 (2000).

    CAS  PubMed  Google Scholar 

  70. Bressan, D. A., Baxter, B. K. & Petrini, J. H. The Mre11-Rad50-Xrs2 protein complex facilitates homologous recombination-based double-strand break repair in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 7681–7687 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wu, X. et al. Independence of R/M/N focus formation and the presence of intact BRCA1. Science 289, 11 (2000).

    CAS  PubMed  Google Scholar 

  72. Resnick, I. B. et al. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J. Pediatr. 140, 355–361 (2002).

    PubMed  Google Scholar 

  73. Nakanishi, K. et al. Interaction of FANCD2 and NBS1 in the DNA damage response. Nature Cell Biol. 4, 913–920 (2002). Shows that NBS1−/− cells have mitomycin C sensitivity, similar to the defect observed in FA cells. Moreover, NBS1 and FANCD2 interact in an S-phase checkpoint function and in repair of DNA crosslinks.

    CAS  PubMed  Google Scholar 

  74. Shimamura, A. et al. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 29 Aug 2002 [epub ahead of print].

  75. Chen, M. et al. Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia. Nature Genet. 12, 448–451 (1996).

    CAS  PubMed  Google Scholar 

  76. Whitney, M. A. et al. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood 88, 49–58 (1996). Describes a knockout of the murine Fancc gene. Primary cells isolated from the knockout animal have chromosome instability and γ-interferon hypersensitivity.

    CAS  PubMed  Google Scholar 

  77. Noll, M. et al. Fanconi anemia group A and C double-mutant mice. Functional evidence for a multi-protein Fanconi anemia complex. Exp. Hematol. 30, 679–688 (2002).

    CAS  PubMed  Google Scholar 

  78. Rio, P. et al. In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice. Blood 100, 2032–2039 (2002).

    CAS  PubMed  Google Scholar 

  79. Yang, Y. et al. Targeted disruption of the murine Fanconi anemia gene, Fancg/Xrcc9. Blood 98, 3435–3440 (2001).

    CAS  PubMed  Google Scholar 

  80. Koomen, M. et al. Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice. Hum. Mol. Genet. 11, 273–281 (2002).

    CAS  PubMed  Google Scholar 

  81. Haneline, L. S. et al. Loss of FancC function results in decreased hematopoietic stem cell repopulating ability. Blood 94, 1–8 (1999).

    CAS  PubMed  Google Scholar 

  82. Haneline, L. S. et al. Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac−/− mice. Blood 91, 4092–4098 (1998).

    CAS  PubMed  Google Scholar 

  83. Rathbun, R. K. et al. Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. Blood 90, 974–985 (1997).

    CAS  PubMed  Google Scholar 

  84. Rathbun, R. K. et al. Interferon-gamma-induced apoptotic responses of fanconi anemia group C hematopoietic progenitor cells involve caspase 8-dependent activation of caspase 3 family members. Blood 96, 4204–4211 (2000).

    CAS  PubMed  Google Scholar 

  85. Carreau, M. et al. Bone marrow failure in the Fanconi anemia group C mouse model after DNA damage. Blood 91, 2737–2744 (1998).

    CAS  PubMed  Google Scholar 

  86. Noll, M., Bateman, R. L., D'Andrea, A. D. & Grompe, M. Preclinical protocol for in vivo selection of hematopoietic stem cells corrected by gene therapy in Fanconi anemia group C. Mol. Ther. 3, 14–23 (2001).

    CAS  PubMed  Google Scholar 

  87. Battaile, K. P. et al. In vivo selection of wild-type hematopoietic stem cells in a murine model of Fanconi anemia. Blood 94, 2151–2158 (1999).

    CAS  PubMed  Google Scholar 

  88. Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nature Genet. 17, 423–430 (1997).

    CAS  PubMed  Google Scholar 

  89. Ludwig, T., Fisher, P., Murty, V. & Efstratiadis, A. Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene 20, 3937–3948 (2001).

    CAS  PubMed  Google Scholar 

  90. Ludwig, T., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 11, 1226–1241 (1997).

    CAS  PubMed  Google Scholar 

  91. Shu, Z., Smith, S., Wang, L., Rice, M. C. & Kmiec, E. B. Disruption of muREC2/RAD51L1 in mice results in early embryonic lethality which can be partially rescued in a p53(−/−) background. Mol. Cell. Biol. 19, 8686–8693 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu, C. Y., Flesken-Nikitin, A., Li, S., Zeng, Y. & Lee, W. H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 10, 1835–1843 (1996).

    CAS  PubMed  Google Scholar 

  93. Shen, S. X. et al. A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene 17, 3115–3124 (1998).

    CAS  PubMed  Google Scholar 

  94. Painter, R. B. Radioresistant DNA synthesis: an intrinsic feature of ataxia telangiectasia. Mutat. Res. 84, 183–190 (1981).

    CAS  PubMed  Google Scholar 

  95. Centurion, S. A., Kuo, H. R. & Lambert, W. C. Damage-resistant DNA synthesis in fanconi anemia cells treated with a DNA cross-linking agent. Exp. Cell Res. 260, 216–221 (2000).

    CAS  PubMed  Google Scholar 

  96. Sala-Trepat, M. et al. Arrest of S-phase progression is impaired in fanconi anemia cells. Exp. Cell Res. 260, 208–215 (2000).

    CAS  PubMed  Google Scholar 

  97. Akkari, Y. M., Bateman, R. L., Reifsteck, C. A., Olson, S. B. & Grompe, M. DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand cross-links. Mol. Cell. Biol. 20, 8283–8289 (2000). Shows that DNA crosslinks cause a cellular arrest in S phase. The data indicate that crosslink repair is mediated by homologous recombination repair in S phase.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Escarceller, M., Rousset, S., Moustacchi, E. & Papadopoulo, D. The fidelity of double strand breaks processing is impaired in complementation groups B and D of Fanconi anemia, a genetic instability syndrome. Somatic Cell Mol. Genet. 23, 401–411 (1997).

    CAS  Google Scholar 

  99. Lundberg, R., Mavinakere, M. & Campbell, C. Deficient DNA end joining activity in extracts from fanconi anemia fibroblasts. J. Biol. Chem. 276, 9543–9549 (2001).

    CAS  PubMed  Google Scholar 

  100. Escarceller, M. et al. Fanconi anemia C gene product plays a role in the fidelity of blunt DNA end-joining. J. Mol. Biol. 279, 375–385 (1998).

    CAS  PubMed  Google Scholar 

  101. Scully, R., Puget, N. & Vlasakova, K. DNA polymerase stalling, sister chromatid recombination and the BRCA genes. Oncogene 19, 6176–6183 (2000).

    CAS  PubMed  Google Scholar 

  102. Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).

    CAS  PubMed  Google Scholar 

  103. Tutt, A. et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 20, 4704–4716 (2001). Shows that Brca1/Fancd1−/− cells have an underlying defect in homologous recombination repair and in sister-chromatid exchange.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Larminat, F., Germanier, M., Papouli, E. & Defais, M. Deficiency in BRCA2 leads to increase in non-conservative homologous recombination. Oncogene 21, 5188–5192 (2002).

    CAS  PubMed  Google Scholar 

  105. Wong, A. K., Pero, R., Ormonde, P. A., Tavtigian, S. V. & Bartel, P. L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene Brca2. J. Biol. Chem. 272, 31941–31944 (1997).

    CAS  PubMed  Google Scholar 

  106. Wilson, J. H. & Elledge, S. J. Cancer: BRCA2 enters the fray. Science 297, 1822–1823 (2002).

    CAS  PubMed  Google Scholar 

  107. Yang, H. et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297, 1837–1848 (2002). Describes the first crystal structure for a domain of a Fanconi anaemia protein, BRCA2/FANCD2. This paper also shows that the carboxyl terminus of the protein has a regulated interaction with DNA.

    CAS  PubMed  Google Scholar 

  108. Scully, R. et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435 (1997).

    CAS  PubMed  Google Scholar 

  109. Zickler, D. & Kleckner, N. Meiotic chromosomes: integrating structure and function. Annu. Rev. Genet. 33, 603–754 (1999).

    CAS  PubMed  Google Scholar 

  110. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    CAS  PubMed  Google Scholar 

  111. Moynahan, M. E., Cui, T. Y. & Jasin, M. Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).

    CAS  PubMed  Google Scholar 

  112. Meyn, S., D'Andrea, A., Grompe, M. & Wang, W. The involvement of Fanconi Anemia proteins in homologous genetic recombination. Am. J. Hum. Genet. 69, 750 (2001).

    Google Scholar 

  113. Thyagarajan, B. & Campbell, C. Elevated homologous recombination activity in fanconi anemia fibroblasts. J. Biol. Chem. 272, 23328–23333 (1997).

    CAS  PubMed  Google Scholar 

  114. Papadopoulo, D., Guillouf, C., Mohrenweiser, H. & Moustacchi, E. Hypomutability in Fanconi anemia cells is associated with increased deletion frequency at the HPRT locus. Proc. Natl Acad. Sci. USA 87, 8383–8387 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sala-Trepat, M., Boyse, J., Richard, P., Papadopoulo, D. & Moustacchi, E. Frequencies of HPRT lymphocytes and glycophorin A variants erythrocytes in Fanconi anemia patients, their parents and control donors. Mut. Res. 289, 115–126 (1993).

    CAS  Google Scholar 

  116. Laquerbe, A., Sala-Trepat, M., Vives, C., Escarceller, M. & Papadopoulo, D. Molecular spectra of HPRT deletion mutations in circulating T-lymphocytes in Fanconi anemia patients. Mutat. Res. 431, 341–350 (1999).

    CAS  PubMed  Google Scholar 

  117. McHugh, P. J., Spanswick, V. J. & Hartley, J. A. Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol. 2, 483–490 (2001).

    CAS  PubMed  Google Scholar 

  118. Wang, X. et al. Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol. Cell. Biol. 21, 713–720 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Bessho, T., Mu, D. & Sancar, A. Initiation of DNA interstrand cross-link repair in humans: the nucleotide excision repair system makes dual incisions 5′ to the cross-linked base and removes a 22- to 28-nucleotide-long damage-free strand. Mol. Cell. Biol. 17, 6822–6830 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. De Silva, I. U., McHugh, P. J., Clingen, P. H. & Hartley, J. A. Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol. Cell. Biol. 20, 7980–7990 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to those authors whose work is not cited owing to space constraints. A.D.D. is a Doris Duke Distinguished Clinical Scientist and is supported by National Institutes of Health grants. M.G. is supported by a National Institutes of Health grant.

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Alan D. D'Andrea

  2. Department of Molecular and Medical Genetics, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road L103, Portland, 97239, Oregon, USA

    Markus Grompe

Authors
  1. Alan D. D'Andrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Grompe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan D. D'Andrea.

Related links

Related links

DATABASES

LocusLink

ATM

BRCA1

BRCA2

FANCA

FANCC

FANCD1

FANCD2

FANCE

FANCF

FANCG

HPGRT

MRE11

NBS1

RAD6

RAD18

RAD51

OMIM

ataxia telangiectasia

Bloom syndrome

Fanconi anaemia

Nijmegen breakage syndrome

Glossary

PANCYTOPAENIA

Greatly decreased levels or absence of primary haematopoietic cells in the bone marrow. In this state, there are decreased numbers of lymphocyte, red blood cell and platelet progenitors.

RADIAL CHROMOSOMES

Abnormal chromosome structures that result from pairing of homologous or non-homologous metaphase chromosomes. These structures are observed in chromosome spreads prepared from cells with underlying chromosome instability, such as cells from patients with Fanconi anaemia, Bloom syndrome and ataxia telangiectasia.

COMPLEMENTATION GROUPS

These subsets of Fanconi anaemia were established by somatic-cell fusion analysis of cells derived from patients with the disease. Two cell lines are members of two different complementation groups if the fused line has complemented or restored its normal cellular phenotype (that is, mitomycin C resistance).

FOUNDER EFFECT

High frequency of a rare genetic mutation in a population. The mutation originally present in a founder individual becomes prevalent by inbreeding.

RING-FINGER DOMAIN

A distinct zinc-binding domain that is present in many E3 ubiquitin ligases. The RING finger binds two zinc atoms, with each atom ligated in a tetrahelix by four cysteines, or three cysteines and one histidine.

HECT DOMAIN

(Homologous to E6-AP carboxyl terminus domain). A distinct domain that is characteristic of another subclass of E3 ubiquitin ligases. Mammalian HECT E3s include E6-AP, which targets p53 for ubiquitylation in the presence of human papillomavirus E6.

HYPOMORPHIC MUTATION

A hypomorphic mutation in a gene partially disrupts the function of the gene. The hypomorphic allele of the gene encodes an abnormal protein with partial cellular function.

SUB-4N DNA CONTENT

A cell with sub-4N DNA content has not completed full DNA replication. By definition, the cell is undergoing DNA replication.

Rights and permissions

Reprints and permissions

About this article

Cite this article

D'Andrea, A., Grompe, M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3, 23–34 (2003). https://doi.org/10.1038/nrc970

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc970

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing