Fanconi anaemia and cancer: an intricate relationship

Key Points

  • Fanconi anaemia (FA) is a complex genetic syndrome associated with risk of congenital malformations, bone marrow failure and cancer. Diagnosis of FA is challenging, as the clinical presentation differs between patients and as other genetic syndromes resemble FA, but a correct diagnosis is needed to optimize clinical care.

  • All patients with FA have a high risk of cancer, particularly acute myeloid leukaemia (AML) and squamous cell carcinoma. Close expert surveillance is needed from early childhood to detect malignancies early, should they occur.

  • FA is caused by inherited mutations in any one of at least 21 genes. Genotype–phenotype correlations in FA are beginning to emerge: patients with FA due to biallelic mutations within BRCA1 or BRCA2 have an increased risk of brain tumours in addition to AML.

  • The FA pathway maximizes efficient DNA damage repair through homologous recombination, coordinates DNA replication and fine-tunes mitotic checkpoints to ensure error-free chromosome segregation during cell division. Therefore, FA proteins guard the genome stability throughout the cell cycle.

  • Impaired DNA damage repair, faulty DNA replication and chromosome mis-segregation together cause genomic instability in cells deficient in the FA pathway, which may lead to p53-dependent cell cycle arrest and bone marrow failure, or if cell cycle checkpoints fail, this instability may lead to propagation of mutations and cancer.

  • Acquired mutations in FA genes occur in malignancies in children and adults who do not have FA. As loss of FA pathway activity renders cancer cells sensitive to inhibition of poly(ADP-ribose) polymerase (PARP) and other signalling pathways, knowledge of the FA pathway status in tumours can be utilized for the rational development of personalized precision medicine cancer therapies.


Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2–FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.

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Figure 1: Fanconi anaemia: a complex genetic disorder with developmental abnormalities, bone marrow failure and cancer.
Figure 2: Somatic Fanconi anaemia gene mutations in cancers of patients without Fanconi anaemia.
Figure 3: The Fanconi anaemia pathway orchestrates the interphase DNA damage response.
Figure 4: The Fanconi anaemia pathway prevents genomic instability and carcinogenesis throughout the cell cycle.


  1. 1

    Lobitz, S. & Velleuer, E. Guido Fanconi (1892–1979): a jack of all trades. Nat. Rev. Cancer 6, 893–898 (2006).

  2. 2

    Ameziane, N. et al. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nat. Commun. 6, 8829 (2015).

  3. 3

    Wang, A. T. et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59, 478–490 (2015).

  4. 4

    Tischkowitz, M. D. et al. Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia. Leukemia 18, 420–425 (2004).

  5. 5

    Tischkowitz, M. et al. Bi-allelic silencing of the Fanconi anaemia gene FANCF in acute myeloid leukaemia. Br. J. Haematol. 123, 469–471 (2003).

  6. 6

    Hess, C. J. et al. Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukaemia. Cell Oncol. 30, 299–306 (2008).

  7. 7

    Alter, B. P. & Rosenberg, P. S. VACTERL-H association and Fanconi anemia. Mol. Syndromol 4, 87–93 (2013).

  8. 8

    Neveling, K., Endt, D., Hoehn, H. & Schindler, D. Genotype-phenotype correlations in Fanconi anemia. Mutat. Res. 668, 73–91 (2009).

  9. 9

    Auerbach, A. D. Fanconi anemia and its diagnosis. Mutat. Res. 668, 4–10 (2009).

  10. 10

    Shimamura, A. & Alter, B. P. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 24, 101–122 (2010).

  11. 11

    Zhu, A. X., D'Andrea, A. D., Sahani, D. V. & Hasserjian, R. P. Case records of the Massachusetts General Hospital. Case 13–2006. A 50-year-old man with a painful bone mass and lesions in the liver. N. Engl. J. Med. 354, 1828–1837 (2006).

  12. 12

    Huck, K. et al. Delayed diagnosis and complications of Fanconi anaemia at advanced age — a paradigm. Br. J. Haematol. 133, 188–197 (2006).

  13. 13

    Rochowski, A. et al. Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy. Leuk. Res. 36, 29–31 (2012).

  14. 14

    Sharma, R. & Nalepa, G. Evaluation and management of chronic pancytopenia. Pediatr. Rev. 37, 101–111 (2016).

  15. 15

    Tamary, H. et al. Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry. Haematologica 95, 1300–1307 (2010).

  16. 16

    Rosenberg, P. S., Tamary, H. & Alter, B. P. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel. Am. J. Med. Genet. A 155A, 1877–1883 (2011).

  17. 17

    Callen, E. et al. A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood 105, 1946–1949 (2005).

  18. 18

    Rosendorff, J., Bernstein, R., Macdougall, L. & Jenkins, T. Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa. Am. J. Med. Genet. 27, 793–797 (1987).

  19. 19

    Yagasaki, H. et al. Two common founder mutations of the fanconi anemia group G gene FANCG/XRCC9 in the Japanese population. Hum. Mutat. 21, 555 (2003).

  20. 20

    Morgan, N. V. et al. A common Fanconi anemia mutation in black populations of sub-Saharan Africa. Blood 105, 3542–3544 (2005).

  21. 21

    Tipping, A. J. et al. Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc. Natl Acad. Sci. USA 98, 5734–5739 (2001).

  22. 22

    Shimamura, A. et al. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 100, 4649–4654 (2002).

  23. 23

    Hays, L. et al. Fanconi Anemia: Guidelines for Diagnosis and Management 4 edn (Fanconi Anemia Research Fund, 2014).

  24. 24

    Kutler, D. I. et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 101, 1249–1256 (2003). This large long-term observational cohort study reports a high risk of cancer (23%) and BMF (80%) in 754 patients with FA over 20 years.

  25. 25

    Paustian, L. et al. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr. Hematol. Oncol. 33, 5–12 (2016).

  26. 26

    Velazquez, I. & Alter, B. P. Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions. Am. J. Hematol. 77, 257–267 (2004).

  27. 27

    Schifferli, A. & Kuhne, T. Fanconi anemia: overview of the disease and the role of hematopoietic transplantation. J. Pediatr. Hematol. Oncol. 37, 335–343 (2015).

  28. 28

    Torjemane, L. et al. Bone marrow transplantation from matched related donors for patients with Fanconi anemia using low-dose busulfan and cyclophosphamide as conditioning. Pediatr. Blood Cancer 46, 496–500 (2006).

  29. 29

    Alter, B. P. Fanconi anemia and the development of leukemia. Best Pract. Res. Clin. Haematol. 27, 214–221 (2014).

  30. 30

    Alter, B. P. et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br. J. Haematol. 150, 179–188 (2010). This study provides quantitative data regarding the risk and spectrum of malignancies in patients with FA and other inherited BMF syndromes enrolled in the National Cancer Institute Inherited BMF Syndromes (IBMFS) registry.

  31. 31

    Kutler, D. I. et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch. Otolaryngol. Head Neck Surg. 129, 106–112 (2003).

  32. 32

    Rosenberg, P. S., Socie, G., Alter, B. P. & Gluckman, E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 105, 67–73 (2005).

  33. 33

    Ellis, N. A. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83, 655–666 (1995).

  34. 34

    Ellis, N. A., Proytcheva, M., Sanz, M. M., Ye, T. Z. & German, J. Transfection of BLM into cultured bloom syndrome cells reduces the sister-chromatid exchange rate toward normal. Am. J. Hum. Genet. 65, 1368–1374 (1999).

  35. 35

    Cunniff, C., Bassetti, J. A. & Ellis, N. A. Bloom's syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol. Syndromol 8, 4–23 (2017).

  36. 36

    Wechsler, T., Newman, S. & West, S. C. Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature 471, 642–646 (2011).

  37. 37

    Naim, V. & Rosselli, F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nature Cell Biol. 11, 761–768 (2009). This study reports that FANCD2 localizes to mitotic anaphase bridges resulting from interphase replication stress and recruits the BLM helicase to prevent chromosome damage and genomic instability.

  38. 38

    Schurman, S. H. et al. Direct and indirect roles of RECQL4 in modulating base excision repair capacity. Hum. Mol. Genet. 18, 3470–3483 (2009).

  39. 39

    Croteau, D. L., Singh, D. K., Hoh Ferrarelli, L., Lu, H. & Bohr, V. A. RECQL4 in genomic instability and aging. Trends Genet. 28, 624–631 (2012).

  40. 40

    Kitao, S. et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat. Genet. 22, 82–84 (1999).

  41. 41

    Van Maldergem, L. et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43, 148–152 (2006).

  42. 42

    Siitonen, H. A. et al. The mutation spectrum in RECQL4 diseases. Eur. J. Hum. Genet. 17, 151–158 (2009).

  43. 43

    Wang, L. L. et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J. Natl Cancer Inst. 95, 669–674 (2003).

  44. 44

    Carlson, A. M., Lindor, N. M. & Litzow, M. R. Therapy-related myelodysplasia in a patient with Rothmund-Thomson syndrome. Eur. J. Haematol. 86, 536–540 (2011).

  45. 45

    Kraemer, K. H. & DiGiovanna, J. J. Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem. Photobiol. 91, 452–459 (2015).

  46. 46

    Bradford, P. T. et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J. Med. Genet. 48, 168–176 (2011).

  47. 47

    Bogliolo, M. et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am. J. Hum. Genet. 92, 800–806 (2013).

  48. 48

    Kashiyama, K. et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am. J. Hum. Genet. 92, 807–819 (2013).

  49. 49

    Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).

  50. 50

    Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).

  51. 51

    Chen, S. & Parmigiani, G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 25, 1329–1333 (2007).

  52. 52

    Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002). This work demonstrates that inactivation of both BRCA2 alleles causes FA, providing direct clinical evidence of the genetic relationship between FA and hereditary breast and ovarian cancer predisposition syndromes.

  53. 53

    Alter, B. P., Rosenberg, P. S. & Brody, L. C. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J. Med. Genet. 44, 1–9 (2007).

  54. 54

    Myers, K. et al. The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. Pediatr. Blood Cancer 58, 462–465 (2012).

  55. 55

    Sawyer, S. L. et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 5, 135–142 (2015).

  56. 56

    Domchek, S. M. et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 3, 399–405 (2013).

  57. 57

    Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

  58. 58

    Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet. 37, 934–935 (2005).

  59. 59

    Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat. Genet. 37, 931–933 (2005).

  60. 60

    Easton, D. F. et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 53, 298–309 (2016).

  61. 61

    Berwick, M. et al. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 67, 9591–9596 (2007).

  62. 62

    Laitman, Y. et al. The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers. Cancer Genet. 209, 70–74 (2016).

  63. 63

    Thompson, E. R. et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 8, e1002894 (2012).

  64. 64

    Couch, F. J. et al. Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 65, 383–386 (2005).

  65. 65

    Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).

  66. 66

    Virts, E. L. et al. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. Hum. Mol. Genet. 24, 5093–5108 (2015).

  67. 67

    Kiiski, J. I. et al. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc. Natl Acad. Sci. USA 111, 15172–15177 (2014).

  68. 68

    Katzke, V. A., Kaaks, R. & Kuhn, T. Lifestyle and cancer risk. Cancer J. 21, 104–110 (2015).

  69. 69

    Umar, A., Dunn, B. K. & Greenwald, P. Future directions in cancer prevention. Nat. Rev. Cancer 12, 835–848 (2012).

  70. 70

    Feinberg, A. P., Koldobskiy, M. A. & Gondor, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).

  71. 71

    Shen, Y. et al. Mutated Fanconi anemia pathway in non-Fanconi anemia cancers. Oncotarget 6, 20396–20403 (2015).

  72. 72

    Xie, Y. et al. Aberrant Fanconi anaemia protein profiles in acute myeloid leukaemia cells. Br. J. Haematol. 111, 1057–1064 (2000).

  73. 73

    van der Heijden, M. S., Yeo, C. J., Hruban, R. H. & Kern, S. E. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 63, 2585–2588 (2003).

  74. 74

    Wreesmann, V. B., Estilo, C., Eisele, D. W., Singh, B. & Wang, S. J. Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma. ORL J. Otorhinolaryngol. Relat. Spec. 69, 218–225 (2007).

  75. 75

    Kais, Z. et al. FANCD2 maintains fork stability in BRCA1/2-deficient tumors and promotes alternative end-joining DNA repair. Cell Rep. 15, 2488–2499 (2016).

  76. 76

    Michl, J., Zimmer, J., Buffa, F. M., McDermott, U. & Tarsounas, M. FANCD2 limits replication stress and genome instability in cells lacking BRCA2. Nat. Struct. Mol. Biol. 23, 755–757 (2016).

  77. 77

    Kauffmann, A. et al. High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene 27, 565–573 (2008).

  78. 78

    Ozawa, H. et al. FANCD2 mRNA overexpression is a bona fide indicator of lymph node metastasis in human colorectal cancer. Ann. Surg. Oncol. 17, 2341–2348 (2010).

  79. 79

    Strub, T. et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene 30, 2319–2332 (2011).

  80. 80

    Bourseguin, J. et al. FANCD2 functions as a critical factor downstream of MiTF to maintain the proliferation and survival of melanoma cells. Sci. Rep. 6, 36539 (2016).

  81. 81

    Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13, 189–203 (2012).

  82. 82

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  83. 83

    Fouad, Y. A. & Aanei, C. Revisiting the hallmarks of cancer. Am. J. Cancer Res. 7, 1016–1036 (2017).

  84. 84

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

  85. 85

    Castro-Giner, F., Ratcliffe, P. & Tomlinson, I. The mini-driver model of polygenic cancer evolution. Nat. Rev. Cancer 15, 680–685 (2015).

  86. 86

    Krem, M. M., Press, O. W., Horwitz, M. S. & Tidwell, T. Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy. Br. J. Haematol. 171, 13–28 (2015).

  87. 87

    Barber, L. J., Davies, M. N. & Gerlinger, M. Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale. Curr. Opin. Genet. Dev. 30, 1–6 (2015).

  88. 88

    Shlush, L. I. & Hershkovitz, D. Clonal evolution models of tumor heterogeneity. Am. Soc. Clin. Oncol. Educ. Book, e662–5 (2015).

  89. 89

    Otto, T. & Sicinski, P. Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer 17, 93–115 (2017).

  90. 90

    Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).

  91. 91

    Salazar-Roa, M. & Malumbres, M. Fueling the cell division cycle. Trends Cell Biol. 27, 69–81 (2017).

  92. 92

    Tomasetti, C. & Vogelstein, B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

  93. 93

    Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).

  94. 94

    Park, E. et al. FANCD2 activates transcription of TAp63 and suppresses tumorigenesis. Mol. Cell 50, 908–918 (2013).

  95. 95

    Awasthi, P., Foiani, M. & Kumar, A. ATM and ATR signaling at a glance. J. Cell Sci. 128, 4255–4262 (2015).

  96. 96

    Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801–817 (2017).

  97. 97

    Warfel, N. A. & El-Deiry, W. S. p21WAF1 and tumourigenesis: 20 years after. Curr. Opin. Oncol. 25, 52–58 (2013).

  98. 98

    Collins, N. B. et al. ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function. Blood 113, 2181–2190 (2009).

  99. 99

    Wang, X. et al. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol. Cell. Biol. 27, 3098–3108 (2007).

  100. 100

    Singh, T. R. et al. ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res. 73, 4300–4310 (2013).

  101. 101

    Xie, J. et al. RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J. Clin. Invest. 125, 1523–1532 (2015).

  102. 102

    Yamamoto, K. N. et al. Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proc. Natl Acad. Sci. USA 108, 6492–6496 (2011).

  103. 103

    Lachaud, C. et al. Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. J. Cell Sci. 127, 2811–2817 (2014).

  104. 104

    Gwon, G. H. et al. Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5′ flap DNA: basis of interstrand cross-link repair by FAN1. Genes Dev. 28, 2276–2290 (2014).

  105. 105

    Sobeck, A. et al. Fanconi anemia proteins are required to prevent accumulation of replication-associated DNA double-strand breaks. Mol. Cell. Biol. 26, 425–437 (2006).

  106. 106

    Helmrich, A., Ballarino, M. & Tora, L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44, 966–977 (2011).

  107. 107

    Segurado, M. & Diffley, J. F. Separate roles for the DNA damage checkpoint protein kinases in stabilizing DNA replication forks. Genes Dev. 22, 1816–1827 (2008).

  108. 108

    Pichierri, P. & Rosselli, F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. EMBO J. 23, 1178–1187 (2004).

  109. 109

    Schwab, R. A. et al. The Fanconi anemia pathway maintains genome stability by coordinating replication and transcription. Mol. Cell 60, 351–361 (2015).

  110. 110

    Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012).

  111. 111

    Deans, A. J. & West, S. C. DNA interstrand crosslink repair and cancer. Nat. Rev. Cancer 11, 467–480 (2011).

  112. 112

    Kim, Y. et al. Mutations of the SLX4 gene in Fanconi anemia. Nat. Genet. 43, 142–146 (2011).

  113. 113

    Stoepker, C. et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat. Genet. 43, 138–141 (2011).

  114. 114

    Wang, R. et al. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1. Science 346, 1127–1130 (2014).

  115. 115

    Smogorzewska, A. et al. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol. Cell 39, 36–47 (2010).

  116. 116

    Long, D. T., Raschle, M., Joukov, V. & Walter, J. C. Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333, 84–87 (2011).

  117. 117

    Vaz, F. et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat. Genet. 42, 406–409 (2010).

  118. 118

    Schwab, R. A., Blackford, A. N. & Niedzwiedz, W. ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J. 29, 806–818 (2010).

  119. 119

    Adamo, A. et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol. Cell 39, 25–35 (2010).

  120. 120

    Pace, P. et al. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329, 219–223 (2010). References 119 and 120 suggest that excessive use of alternative repair strategies based on non-HR owing to defective HR-based repair is detrimental to cells deficient in the FA pathway.

  121. 121

    Renaud, E., Barascu, A. & Rosselli, F. Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells. Nucleic Acids Res. 44, 648–656 (2016).

  122. 122

    Blunt, T. et al. Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc. Natl Acad. Sci. USA 93, 10285–10290 (1996).

  123. 123

    Houghtaling, S. et al. Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining. Hum. Mol. Genet. 14, 3027–3033 (2005).

  124. 124

    Bunting, S. F. et al. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol. Cell 46, 125–135 (2012).

  125. 125

    Ceccaldi, R., Sarangi, P. & D'Andrea, A. D. The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol. 17, 337–349 (2016).

  126. 126

    Lossaint, G. et al. FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling. Mol. Cell 51, 678–690 (2013).

  127. 127

    Nalepa, G. et al. Fanconi anemia signaling network regulates the spindle assembly checkpoint. J. Clin. Invest. 123, 3839–3847 (2013). This study shows an impaired SAC and accumulation of supernumerary centrosomes in primary cells of patients with FA owing to mutations in 1 of 12 different FA genes, implicating the FA pathway in genome maintenance through control of the centrosome cycle and cell division beyond the interphase DDR.

  128. 128

    Nam, H. J., Naylor, R. M. & van Deursen, J. M. Centrosome dynamics as a source of chromosomal instability. Trends Cell Biol. 25, 65–73 (2015).

  129. 129

    Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009).

  130. 130

    de Carcer, G. & Malumbres, M. A centrosomal route for cancer genome instability. Nature Cell Biol. 16, 504–506 (2014).

  131. 131

    Abdul-Sater, Z. et al. FANCA safeguards interphase and mitosis during hematopoiesis in vivo. Exp. Hematol. 43, 1031–1046.e12 (2015).

  132. 132

    Vinciguerra, P., Godinho, S. A., Parmar, K., Pellman, D. & D'Andrea, A. D. Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. J. Clin. Invest. 120, 3834–3842 (2010). This work demonstrates that at least some FA proteins function beyond the recognized interphase DDR in cytokinesis.

  133. 133

    Zou, J. et al. FancJ regulates interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1. Biol. Open 2, 1022–1031 (2013).

  134. 134

    Kim, S. et al. Fanconi anemia complementation group A (FANCA) localizes to centrosomes and functions in the maintenance of centrosome integrity. Int. J. Biochem. Cell Biol. 45, 1953–1961 (2013).

  135. 135

    Wang, H. F., Takenaka, K., Nakanishi, A. & Miki, Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 71, 68–77 (2011).

  136. 136

    Magron, A., Elowe, S. & Carreau, M. The Fanconi anemia C protein binds to and regulates Stathmin-1 phosphorylation. PLoS ONE 10, e0140612 (2015).

  137. 137

    Kupfer, G. M. et al. The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2. Blood 90, 1047–1054 (1997). This paper describes the physical interaction between FANCC and the key mitotic CDK, CDK1.

  138. 138

    Beretta, L., Dobransky, T. & Sobel, A. Multiple phosphorylation of stathmin. Identification of four sites phosphorylated in intact cells and in vitro by cyclic AMP-dependent protein kinase and p34cdc2. J. Biol. Chem. 268, 20076–20084 (1993).

  139. 139

    Godek, K. M., Kabeche, L. & Compton, D. A. Regulation of kinetochore-microtubule attachments through homeostatic control during mitosis. Nat. Rev. Mol. Cell Biol. 16, 57–64 (2015).

  140. 140

    London, N. & Biggins, S. Signalling dynamics in the spindle checkpoint response. Nat. Rev. Mol. Cell Biol. 15, 736–747 (2014).

  141. 141

    Choi, E. et al. BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation. Dev. Cell 22, 295–308 (2012). This work suggests that the mechanism of action of one of the FA proteins, BRCA2, is in the activation of the SAC.

  142. 142

    Park, I. et al. Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation. J. Cell Biol. 202, 295–309 (2013).

  143. 143

    Chan, K. L., Palmai-Pallag, T., Ying, S. & Hickson, I. D. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nature Cell Biol. 11, 753–760 (2009). This work identifies that the FANCD2–FANCI heterodimer colocalizes with the BLM helicase on mitotic chromosome bridges induced by replication stress, implicating the FA and BLM protein pathways in the prevention of micronucleation and genomic instability throughout the cell cycle.

  144. 144

    Guervilly, J. H. et al. The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Mol. Cell 57, 123–137 (2015).

  145. 145

    Ouyang, J. et al. Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol. Cell 57, 108–122 (2015).

  146. 146

    Ouyang, K. J. et al. SUMO modification regulates BLM and RAD51 interaction at damaged replication forks. PLoS Biol. 7, e1000252 (2009).

  147. 147

    Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012). This work elegantly describes how micronucleation resulting from chromosome mis-segregation during cell division fuels excessive mutagenesis in subsequent interphase.

  148. 148

    Daniels, M. J., Wang, Y., Lee, M. & Venkitaraman, A. R. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876–879 (2004). This paper shows that BRCA2 controls the cell cycle beyond the interphase DDR.

  149. 149

    Jonsdottir, A. B. et al. Tetraploidy in BRCA2 breast tumours. Eur. J. Cancer 48, 305–310 (2012).

  150. 150

    Jonsdottir, A. B. et al. BRCA2 heterozygosity delays cytokinesis in primary human fibroblasts. Cell Oncol. 31, 191–201 (2009).

  151. 151

    Takaoka, M., Saito, H., Takenaka, K., Miki, Y. & Nakanishi, A. BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC. Cancer Res. 74, 1518–1528 (2014).

  152. 152

    Mondal, G. et al. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev. Cell 23, 137–152 (2012).

  153. 153

    Pawlikowska, P., Fouchet, P., Vainchenker, W., Rosselli, F. & Naim, V. Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca−/− mice. Blood 124, 3613–3623 (2014).

  154. 154

    Alavattam, K. G. et al. Elucidation of the Fanconi anemia protein network in meiosis and its function in the regulation of histone modifications. Cell Rep. 17, 1141–1157 (2016).

  155. 155

    Kato, Y. et al. FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis. Hum. Mol. Genet. 24, 5234–5249 (2015).

  156. 156

    Cuomo, M. E. et al. p53-driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nature Cell Biol. 10, 723–730 (2008).

  157. 157

    Mikule, K. et al. Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest. Nature Cell Biol. 9, 160–170 (2007).

  158. 158

    Ceccaldi, R. et al. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 11, 36–49 (2012). This study demonstrates that inhibition of p53-induced cell cycle arrest promotes proliferation of cells with deficiencies in the FA pathway ex vivo and in vivo , implicating the p53 DDR in FA-associated BMF.

  159. 159

    Ceccaldi, R. et al. Spontaneous abrogation of the G2DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients. J. Clin. Invest. 121, 184–194 (2011).

  160. 160

    Freie, B. et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood 102, 4146–4152 (2003). This study shows that Fancc−/− mice develop a variety of malignancies upon Trp53 -knockout, highlighting the importance of a functional p53 pathway in preventing FA-associated cancers in vivo.

  161. 161

    Woo, H. I. et al. Acute myeloid leukemia with complex hypodiploidy and loss of heterozygosity of 17p in a boy with Fanconi anemia. Ann. Clin. Lab Sci. 41, 66–70 (2011).

  162. 162

    Quentin, S. et al. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood 117, e161–170 (2011).

  163. 163

    Zanier, R., Briot, D., Dugas du Villard, J. A., Sarasin, A. & Rosselli, F. Fanconi anemia C gene product regulates expression of genes involved in differentiation and inflammation. Oncogene 23, 5004–5013 (2004).

  164. 164

    Rathbun, R. K. et al. Interferon-γ-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).

  165. 165

    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).

  166. 166

    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).

  167. 167

    Li, J. et al. TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. J. Clin. Invest. 117, 3283–3295 (2007).

  168. 168

    Du, W., Erden, O. & Pang, Q. TNF-α signaling in Fanconi anemia. Blood Cells Mol. Dis. 52, 2–11 (2014).

  169. 169

    Fagerlie, S. R. & Bagby, G. C. Immune defects in Fanconi anemia. Crit. Rev. Immunol. 26, 81–96 (2006).

  170. 170

    Sies, H. Oxidative stress: a concept in redox biology and medicine. Redox Biol. 4, 180–183 (2015).

  171. 171

    Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).

  172. 172

    Fritz, K. S. & Petersen, D. R. An overview of the chemistry and biology of reactive aldehydes. Free Radic. Biol. Med. 59, 85–91 (2013).

  173. 173

    Kumari, U., Ya Jun, W., Huat Bay, B. & Lyakhovich, A. Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi anemia cells. Oncogene 33, 165–172 (2014).

  174. 174

    Baan, R. et al. Carcinogenicity of alcoholic beverages. Lancet Oncol. 8, 292–293 (2007).

  175. 175

    Phillips, D. H. & Venitt, S. DNA and protein adducts in human tissues resulting from exposure to tobacco smoke. Int. J. Cancer 131, 2733–2753 (2012).

  176. 176

    Chang, J. S., Hsiao, J. R. & Chen, C. H. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J. Biomed. Sci. 24, 19 (2017).

  177. 177

    Klyosov, A. A., Rashkovetsky, L. G., Tahir, M. K. & Keung, W. M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism. Biochemistry 35, 4445–4456 (1996).

  178. 178

    Brooks, P. J., Enoch, M. A., Goldman, D., Li, T. K. & Yokoyama, A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 6, e50 (2009).

  179. 179

    Harada, S., Agarwal, D. P. & Goedde, H. W. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 2, 982 (1981).

  180. 180

    Joenje, H., Arwert, F., Eriksson, A. W., de Koning, H. & Oostra, A. B. Oxygen-dependence of chromosomal aberrations in Fanconi's anaemia. Nature 290, 142–143 (1981). This is the first paper to demonstrate that chromosome breakage in cells with deficiencies in the FA pathway is exacerbated by oxygen exposure.

  181. 181

    Pagano, G. et al. Bone marrow cell transcripts from Fanconi anaemia patients reveal in vivo alterations in mitochondrial, redox and DNA repair pathways. Eur. J. Haematol. 91, 141–151 (2013).

  182. 182

    Du, W. et al. The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters. Blood 119, 4142–4151 (2012).

  183. 183

    Mukhopadhyay, S. S. et al. Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia. J. Cell Biol. 175, 225–235 (2006).

  184. 184

    Saadatzadeh, M. R., Bijangi-Vishehsaraei, K., Hong, P., Bergmann, H. & Haneline, L. S. Oxidant hypersensitivity of Fanconi anemia type C-deficient cells is dependent on a redox-regulated apoptotic pathway. J. Biol. Chem. 279, 16805–16812 (2004).

  185. 185

    Uziel, O. et al. Oxidative stress causes telomere damage in Fanconi anaemia cells — a possible predisposition for malignant transformation. Br. J. Haematol. 142, 82–93 (2008).

  186. 186

    Pagano, G. et al. In vitro hypersensitivity to oxygen of Fanconi anemia (FA) cells is linked to ex vivo evidence for oxidative stress in FA homozygotes and heterozygotes. Blood 89, 1111–1112 (1997).

  187. 187

    Wilson, H. D., Wilson, J. R. & Fuchs, P. N. Hyperbaric oxygen treatment decreases inflammation and mechanical hypersensitivity in an animal model of inflammatory pain. Brain Res. 1098, 126–128 (2006).

  188. 188

    Hadjur, S. et al. Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase. Blood 98, 1003–1011 (2001).

  189. 189

    Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J. & Patel, K. J. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475, 53–58 (2011).

  190. 190

    Garaycoechea, J. I. et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489, 571–575 (2012). References 189 and 190 demonstrate that deletion of Aldh2 exacerbates perinatal lethality, predisposition to leukaemia and alcohol-induced BMF, and impaired HSC fitness in Fancd2−/− mice, implicating endogenous aldehydes and alcohol intake in in vivo manifestations of FA.

  191. 191

    Oberbeck, N. et al. Maternal aldehyde elimination during pregnancy preserves the fetal genome. Mol. Cell 55, 807–817 (2014).

  192. 192

    Pontel, L. B. et al. Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Mol. Cell 60, 177–188 (2015).

  193. 193

    Hira, A. et al. Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. Blood 122, 3206–3209 (2013). This work demonstrates how a candidate modifier gene may affect the clinical course of FA in a susceptible population, lending clinical support to the proposed role of aldehyde-mediated oxidative stress in the pathogenesis of FA.

  194. 194

    Brooks, P. J. & Zakhari, S. Acetaldehyde and the genome: beyond nuclear DNA adducts and carcinogenesis. Environ. Mol. Mutag. 55, 77–91 (2014).

  195. 195

    Zhang, Q. S. et al. Fancd2−/− mice have hematopoietic defects that can be partially corrected by resveratrol. Blood 116, 5140–5148 (2010).

  196. 196

    Zhang, Q. S. et al. Evaluation of resveratrol and N-acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model. Pediatr. Blood Cancer 61, 740–742 (2014).

  197. 197

    Hamidieh, A. A. et al. Calcitriol for oral mucositis prevention in patients with fanconi anemia undergoing hematopoietic SCT: a double-blind, randomized, placebo-controlled trial. Am. J. Ther. 23, e1700–e1708 (2016).

  198. 198

    Nam, J. S. et al. Application of bioactive quercetin in oncotherapy: from nutrition to nanomedicine. Molecules 21, E108 (2016).

  199. 199

    Leyva-Lopez, N., Gutierrez-Grijalva, E. P., Ambriz-Perez, D. L. & Heredia, J. B. Flavonoids as cytokine modulators: a possible therapy for inflammation-related diseases. Int. J. Mol. Sci. 17, E921 (2016).

  200. 200

    US National Library of Medicine. (2017).

  201. 201

    Taniguchi, T. et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat. Med. 9, 568–574 (2003). This work demonstrates that somatic inactivation of the FA pathway occurs in a fraction of primary ovarian tumour cells and cell lines, suggesting a rationale for future targeted therapies.

  202. 202

    Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

  203. 203

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). References 202 and 203 demonstrate that single-agent PARP inhibition selectively inhibits BRCA2-deficient and BRCA1-deficient tumour growth in mouse xenografts and kills tumour cells, confirming the clinically important synthetic lethality between loss of BRCA tumour suppressors and inhibition of PARP.

  204. 204

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009). This is a clinical study that demonstrates the antitumour activity of a PARP inhibitor in patients with inherited BRCA1 and BRCA2 mutations.

  205. 205

    Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

  206. 206

    Chen, C. C., Kennedy, R. D., Sidi, S., Look, A. T. & D'Andrea, A. CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol. Cancer 8, 24 (2009).

  207. 207

    Kennedy, R. D. et al. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J. Clin. Invest. 117, 1440–1449 (2007).

  208. 208

    Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).

  209. 209

    Kim, G. et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline brca-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res. 21, 4257–4261 (2015).

  210. 210

    Konstantinopoulos, P. A. et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J. Clin. Oncol. 28, 3555–3561 (2010).

  211. 211

    Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2014).

  212. 212

    Ledermann, J. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366, 1382–1392 (2012). References 211 and 212 present an initial phase II study demonstrating improved progression-free survival in patients with progressive ovarian cancers treated with PARP inhibitors. This effect was not limited to patients with inherited BRCA1 or BRCA2 mutations, suggesting that tumours with acquired loss of BRCA genes will respond to PARP inhibition as well.

  213. 213

    Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1274–1284 (2017).

  214. 214

    US National Library of Medicine. (2017).

  215. 215

    US National Library of Medicine. (2017).

  216. 216

    US National Library of Medicine. (2017).

  217. 217

    Patil, A. A. et al. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents. Oncotarget 5, 6414–6424 (2014).

  218. 218

    Chirnomas, D. et al. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol. Cancer Ther. 5, 952–961 (2006).

  219. 219

    Landais, I. et al. Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors. Mol. Cancer 8, 133 (2009).

  220. 220

    Malric, A. et al. Fanconi anemia and solid malignancies in childhood: a national retrospective study. Pediatr. Blood Cancer 62, 463–470 (2015).

  221. 221

    Dodgshun, A. J., Sexton-Oates, A., Saffery, R. & Sullivan, M. J. Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. Cancer Genet. 209, 53–56 (2016).

  222. 222

    Hirsch, B. et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 103, 2554–2559 (2004).

  223. 223

    Wagner, J. E. et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood 103, 3226–3229 (2004).

  224. 224

    Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

  225. 225

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

  226. 226

    Futaki, M. et al. The IVS4 + 4 A to T mutation of the fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Blood 95, 1493–1498 (2000).

  227. 227

    Parmar, K., D'Andrea, A. & Niedernhofer, L. J. Mouse models of Fanconi anemia. Mutat. Res. 668, 133–140 (2009).

  228. 228

    Pulliam-Leath, A. C. et al. Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia. Blood 116, 2915–2920 (2010).

  229. 229

    Walter, D. et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 520, 549–552 (2015).

  230. 230

    Cerabona, D., Sun, Z. & Nalepa, G. Leukemia and chromosomal instability in aged Fancc−/− mice. Exp. Hematol. 44, 352–357 (2016).

  231. 231

    Qiao, F. et al. Phosphorylation of fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. J. Biol. Chem. 279, 46035–46045 (2004).

  232. 232

    Wilson, J. B. et al. Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance. Mutat. Res. 689, 12–20 (2010).

  233. 233

    Ho, G. P., Margossian, S., Taniguchi, T. & D'Andrea, A. D. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol. Cell. Biol. 26, 7005–7015 (2006).

  234. 234

    Ishiai, M. et al. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat. Struct. Mol. Biol. 15, 1138–1146 (2008).

  235. 235

    Andreassen, P. R., D'Andrea, A. D. & Taniguchi, T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 18, 1958–1963 (2004).

  236. 236

    Taniguchi, T. et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109, 459–472 (2002). References 235 and 236 demonstrate ATM-dependent phosphorylation and ATR-dependent monoubiquitylation of FANCD2, providing links between the DDR and the activation of key FA pathway proteins.

  237. 237

    Zhi, G. et al. Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction. Cancer Res. 69, 8775–8783 (2009).

  238. 238

    Smogorzewska, A. et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129, 289–301 (2007). This work identifies FANCI as an FANCD2 monoubiquitylation partner in the DDR–FA signalling pathway.

  239. 239

    Garcia-Higuera, I. et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol. Cell 7, 249–262 (2001). This paper is one of the first to demonstrate the DNA damage-dependent and FA core complex- dependent monoubiquitylation of FANCD2 and the colocalization of FANCD2 and BRCA1 on nuclear damage-induced foci, suggesting a functional connection between these critical tumour-suppressor pathways, which is now well established.

  240. 240

    Meetei, A. R. et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat. Genet. 35, 165–170 (2003).

  241. 241

    Cole, A. R., Lewis, L. P. & Walden, H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat. Struct. Mol. Biol. 17, 294–298 (2010).

  242. 242

    Machida, Y. J. et al. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol. Cell 23, 589–596 (2006).

  243. 243

    Hira, A. et al. Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am. J. Hum. Genet. 96, 1001–1007 (2015).

  244. 244

    Rickman, K. A. et al. Deficiency of UBE2T, the E2 ubiquitin ligase necessary for FANCD2 and FANCI ubiquitination, causes FA-T subtype of Fanconi anemia. Cell Rep. 12, 35–41 (2015).

  245. 245

    Nijman, S. M. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005).

  246. 246

    Gibbs-Seymour, I. et al. Ubiquitin-SUMO circuitry controls activated fanconi anemia ID complex dosage in response to DNA damage. Mol. Cell 57, 150–164 (2015).

  247. 247

    Kim, J. M. et al. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev. Cell 16, 314–320 (2009).

  248. 248

    Parmar, K. et al. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells 28, 1186–1195 (2010).

  249. 249

    Liang, Q. et al. A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses. Nat. Chem. Biol. 10, 298–304 (2014).

  250. 250

    Bogliolo, M. & Surralles, J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr. Opin. Genet. Dev. 33, 32–40 (2015).

  251. 251

    Bluteau, D. et al. Biallelic inactivation of REV7 is associated with Fanconi anemia. J. Clin. Invest. 126, 3580–3584 (2016).

  252. 252

    Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).

  253. 253

    Dror, Y. et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann. NY Acad. Sci. 1242, 40–55 (2011).

  254. 254

    Stanley, S. E. & Armanios, M. The short and long telomere syndromes: paired paradigms for molecular medicine. Curr. Opin. Genet. Dev. 33, 1–9 (2015).

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The authors apologize to the colleagues whose work was not cited owing to space limitations. The authors thank the patients with Fanconi anaemia and their families for generously providing cells used for research in the laboratory of G.N. The authors thank G. H. Vance (Indiana University (IU) School of Medicine) for sharing unpublished images of the chromosome breakage test and D. Carlton (IU School of Medicine) for preparing bone marrow aspirate slides. G.N. is a St. Baldrick's scholar and is supported by the US National Institutes of Health (NIH) and Bone Marrow Failure/Barth Syndrome Fund at Riley Children's Foundation.

Author information

G.N. and D.W.C. researched the data for the article and contributed equally to writing the article and to review and/or editing of the manuscript before submission.

Correspondence to Grzegorz Nalepa or D. Wade Clapp.

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Competing interests

The authors declare no competing financial interests.

PowerPoint slides



Decreased counts of at least two out of three major blood cell types (white blood cells, red blood cells and platelets).

Founder effects

A phenomenon whereby a mutation is present in ancestors of a new population through migration to a geographically distant site or cultural isolation. Upon transmission to the future generations, this mutation might contribute to the newly increased frequency of a genetic disease in the population, particularly if this population remains isolated or if inbreeding limits the influx of normal copies of the gene.

DNA interstrand crosslinking agents

Molecules promoting the formation of covalent bonds between strands of DNA. DNA crosslinks damage the DNA through distortion of the double-helix structure and promote DNA breaks.

Holliday junctions

Intermediate crossed-strand structures between four strands of DNA that arise during homologous recombination through pairing of homologous DNA strands.

Synthetic lethal

A situation where simultaneous mutation of two genes leads to cell death, while mutations in either of these genes alone do not kill the cell.

Standardized incidence ratio

(SIR). The ratio of the observed number of patients to the expected number of cases in a studied population.

Ataxia-telangiectasia mutated

(ATM). A DNA damage sensor kinase activated upon detection of double-stranded DNA breaks. Inherited ATM mutations cause ataxia telangiectasia, an autosomal recessive syndrome of progressive neurological dysfunction, radiation hypersensitivity, telangiectasia (dilated blood vessels) and high risk of cancer.

Ataxia telangiectasia and RAD3-related

(ATR). A DNA damage kinase essential for the DNA damage response (DDR) and error-free replication. Loss of ATR causes Seckel syndrome, a rare autosomal recessive disorder associated with short stature, microcephaly and facial dysmorphism.

Homologous recombination

(HR). A DNA repair mechanism that replaces the lesion with a correct copy created on the template of the undamaged copy of the homologous DNA sequence.

Non-homologous end-joining

(NHEJ). A DNA repair mechanism that corrects double-stranded DNA breaks without using the homologous DNA template to reconstruct the damaged molecule. It is more prone to errors than repair by homologous recombination.


A protein that recognizes and binds double-stranded DNA breaks to activate their repair via the non-homologous end-joining (NHEJ) pathway.

TP53-binding protein 1

(TP53BP1). A protein that positively regulates the DNA damage response (DDR) by activating p53 and interacting with other components of the DDR machinery.


A multiprotein structure that forms on centromeres during cell division to capture spindle microtubules and facilitate segregation of chromosomes.

Mitotic spindle

A highly organized, dynamic cytoskeletal structure that forms from reorganized microtubules, centrosomes and multiple accessory proteins during cell division to segregate chromosomes into the nascent cells.

Spindle assembly checkpoint

(SAC). A signalling pathway that does not allow chromosome segregation to begin until all chromosomes are correctly attached to the mitotic spindle.


A dynamic structure that governs the separation of the cytoplasmic bridge connecting two cells at the end of cell division. Contraction and separation of the midbody complete the separation of daughter cells.


A complex structure within the chromosome that joins chromatids after replication and provides a platform to establish the kinetochore during cell division.


The generation of additional small nuclei, which may occur upon faulty DNA segregation during cell division.

Chromosome pulverization

Extensive shattering of chromosomes into very small fragments owing to abnormal replication and cell division.


The final stage of cell division, during which the cytoplasm of the parental cell is divided between two daughter cells as they separate.


Mitosis not followed by cytokinesis, creating cells with double the amount of DNA.

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Nalepa, G., Clapp, D. Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer 18, 168–185 (2018).

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