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Fanconi anemia, complementation group M
Alt. symbolsKIAA1596
Other data
EC number3.6.1.-
LocusChr. 14 q21.3

Fanconi anemia, complementation group M, also known as FANCM is a human gene.[1][2]


The protein encoded by this gene, FANCM displays DNA binding against fork structures[3] and an ATPase activity associated with DNA branch migration. It is believed that FANCM in conjunction with other Fanconi anemia- proteins repair DNA at stalled replication forks, and stalled transcription structures called R-loops.[4][5]

The structure of the C-terminus of FANCM (amino acids 1799-2048), bound to a partner protein FAAP24, reveals how the protein complex recognises branched DNA.[3] A structure of amino acids 675-790 of FANCM reveal how the protein binds duplex DNA through a remodeling of the MHF1:MHF2 histone-like protein complex.

FANCM crystal structures
Mechanism by which FANCM interacts with DNA, determined by protein crystallography of DNA bound protein fragments[3][6]

Disease linkage[edit]

Homozygous mutations in the FANCM gene are associated with Fanconi anemia, although several individuals with FANCM deficiency do not appear to have the disorder.[7][8][9] A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers.[10] FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours[11]


A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of a homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and Homologous recombination). The pathway leading to a NCO is referred to as synthesis dependent strand annealing (SDSA).

In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants.[12] The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana.[13] A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination.[12] These two pathways likely act by unwinding different joint molecule substrates (e.g. nascent versus extended D-loops; see Figure).

Only about 4% of DSBs in A. thaliana are repaired by CO recombination;[13] the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al.[12] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.

In the fission yeast Schizosaccharomyces pombe, FANCM helicase also directs NCO recombination during meiosis.[14]


  1. ^ Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O (August 2000). "Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (4): 273–81. doi:10.1093/dnares/7.4.271. PMID 10997877.
  2. ^ Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, et al. (September 2005). "A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M". Nature Genetics. 37 (9): 958–63. doi:10.1038/ng1626. PMC 2704909. PMID 16116422.
  3. ^ a b c Coulthard R, Deans AJ, Swuec P, Bowles M, Costa A, West SC, McDonald NQ (September 2013). "Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex". Structure. 21 (9): 1648–58. doi:10.1016/j.str.2013.07.006. PMC 3763369. PMID 23932590.
  4. ^ Gari K, Décaillet C, Stasiak AZ, Stasiak A, Constantinou A (January 2008). "The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks". Molecular Cell. 29 (1): 141–8. doi:10.1016/j.molcel.2007.11.032. PMID 18206976.
  5. ^ Deans AJ, West SC (December 2009). "FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia". Molecular Cell. 36 (6): 943–53. doi:10.1016/j.molcel.2009.12.006. PMID 20064461.
  6. ^ Walden H, Deans AJ (2014). "The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder". Annual Review of Biophysics. 43: 257–78. doi:10.1146/annurev-biophys-051013-022737. PMID 24773018.
  7. ^ Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, et al. (May 2003). "A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome". Molecular and Cellular Biology. 23 (10): 3417–26. doi:10.1128/MCB.23.10.3417-3426.2003. PMC 164758. PMID 12724401.
  8. ^ Bogliolo M, Bluteau D, Lespinasse J, Pujol R, Vasquez N, d'Enghien CD, et al. (April 2018). "Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia". Genetics in Medicine. 20 (4): 458–463. doi:10.1038/gim.2017.124. PMID 28837157.
  9. ^ Catucci I, Osorio A, Arver B, Neidhardt G, Bogliolo M, Zanardi F, et al. (April 2018). "Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility". Genetics in Medicine. 20 (4): 452–457. doi:10.1038/gim.2017.123. PMID 28837162.
  10. ^ Kiiski JI, Pelttari LM, Khan S, Freysteinsdottir ES, Reynisdottir I, Hart SN, et al. (October 2014). "Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer". Proceedings of the National Academy of Sciences of the United States of America. 111 (42): 15172–7. doi:10.1073/pnas.1407909111. PMC 4210278. PMID 25288723.
  11. ^ Dicks E, Song H, Ramus SJ, Oudenhove EV, Tyrer JP, Intermaggio MP, et al. (August 2017). "FANCM as a likely high grade serous ovarian cancer susceptibility gene". Oncotarget. 8 (31): 50930–50940. doi:10.18632/oncotarget.15871. PMC 5584218. PMID 28881617.
  12. ^ a b c Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, et al. (April 2015). "Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM". Proceedings of the National Academy of Sciences of the United States of America. 112 (15): 4713–8. doi:10.1073/pnas.1423107112. PMC 4403193. PMID 25825745.
  13. ^ a b Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, et al. (June 2012). "FANCM limits meiotic crossovers". Science. 336 (6088): 1588–90. doi:10.1126/science.1220381. PMID 22723424.
  14. ^ Lorenz A, Osman F, Sun W, Nandi S, Steinacher R, Whitby MC (June 2012). "The fission yeast FANCM ortholog directs non-crossover recombination during meiosis". Science. 336 (6088): 1585–8. doi:10.1126/science.1220111. PMC 3399777. PMID 22723423.

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