FANCM

The protein encoded by this gene, FANCM displays DNA binding against fork structures{{cite journal | vauthors = Coulthard R, Deans AJ, Swuec P, Bowles M, Costa A, West SC, McDonald NQ | title = Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex | journal = Structure | volume = 21 | issue = 9 | pages = 1648–58 | date = September 2013 | pmid = 23932590 | pmc = 3763369 | doi = 10.1016/j.str.2013.07.006 }} 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.{{cite journal | vauthors = Gari K, Décaillet C, Stasiak AZ, Stasiak A, Constantinou A | title = The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks | journal = Molecular Cell | volume = 29 | issue = 1 | pages = 141–8 | date = January 2008 | pmid = 18206976 | doi = 10.1016/j.molcel.2007.11.032 | doi-access = free }}{{cite journal | vauthors = Deans AJ, West SC | title = FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia | journal = Molecular Cell | volume = 36 | issue = 6 | pages = 943–53 | date = December 2009 | pmid = 20064461 | doi = 10.1016/j.molcel.2009.12.006 | doi-access = free }}

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. 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.

File:FANCM structures sml.jpg

Bi-allelic mutations in the FANCM gene were originally associated with Fanconi anemia, although several individuals with FANCM deficiency do not appear to have the disorder.{{cite journal | vauthors = Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W | display-authors = 6 | title = A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome | journal = Molecular and Cellular Biology | volume = 23 | issue = 10 | pages = 3417–26 | date = May 2003 | pmid = 12724401 | pmc = 164758 | doi = 10.1128/MCB.23.10.3417-3426.2003 }}{{cite journal | vauthors = Bogliolo M, Bluteau D, Lespinasse J, Pujol R, Vasquez N, d'Enghien CD, Stoppa-Lyonnet D, Leblanc T, Soulier J, Surrallés J | display-authors = 6 | title = Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia | journal = Genetics in Medicine | volume = 20 | issue = 4 | pages = 458–463 | date = April 2018 | pmid = 28837157 | doi = 10.1038/gim.2017.124 | s2cid = 4707069 | doi-access = free }}{{cite journal | vauthors = Catucci I, Osorio A, Arver B, Neidhardt G, Bogliolo M, Zanardi F, Riboni M, Minardi S, Pujol R, Azzollini J, Peissel B, Manoukian S, De Vecchi G, Casola S, Hauke J, Richters L, Rhiem K, Schmutzler RK, Wallander K, Törngren T, Borg Å, Radice P, Surrallés J, Hahnen E, Ehrencrona H, Kvist A, Benitez J, Peterlongo P | display-authors = 6 | title = Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility | journal = Genetics in Medicine | volume = 20 | issue = 4 | pages = 452–457 | date = April 2018 | pmid = 28837162 | doi = 10.1038/gim.2017.123 | url = https://ddd.uab.cat/pub/artpub/2018/182643/genmed_a2018v20p452.pdf | doi-access = free }} Mono-allelic FANCM mutations are associated with breast cancer risk and especially with risk of developing ER-negative and TNBC disease subtypes.{{cite journal | vauthors = Peterlongo P, Catucci I, Colombo M, Caleca L, Mucaki E, Bogliolo M, Marin M, Damiola F, Bernard L, Pensotti V, Volorio S, Dall'Olio V, Meindl A, Bartram C, Sutter C, Surowy H, Sornin V, Dondon MG, Eon-Marchais S, Stoppa-Lyonnet D, Andrieu N, Sinilnikova OM, GENESIS, Mitchell G, James PA, Thompson E, kConFab, SWE-BRCA, Marchetti M, Verzeroli C, Tartari C, Capone GL, Putignano AL, Genuardi M, Medici V, Marchi I, Federico M, Tognazzo S, Matricardi L, Agata S, Dolcetti R, Della Puppa L, Cini G, Gismondi V, Viassolo V, Perfumo C, Mencarelli MA, Baldassarri M, Peissel B, Roversi G, Silvestri V, Rizzolo P, Spina F, Vivanet C, Tibiletti MG, Caligo MA, Gambino G, Tommasi S, Pilato B, Tondini C, Corna C, Bonanni B, Barile M, Osorio A, Benitez J, Balestrino L, Ottini L, Manoukian S, Pierotti MA, Renieri A, Varesco L, Couch FJ, Wang X, Devilee P, Hilbers FS, van Asperen CJ, Viel A, Montagna M, Cortesi L, Diez O, Balmaña J, Hauke J, Schmutzler RK, Papi L, Pujana MA, Lázaro C, Falanga A, Offit K, Vijai J, Campbell I, Burwinkel B, Kvist A, Ehrencrona H, Mazoyer S, Pizzamiglio S, Verderio P, Surralles J, Rogan PK, Radice P | display-authors = 6 | title = FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor | journal = Human Molecular Genetics | volume = 24 | issue = 18 | pages = 5345–55 | date = September 2015 | pmid = 26130695 | pmc = 4550823 | doi = 10.1093/hmg/ddv251 }}{{cite journal | vauthors = Neidhardt G, Hauke J, Ramser J, Groß E, Gehrig A, Müller CR, Kahlert AK, Hackmann K, Honisch E, Niederacher D, Heilmann-Heimbach S, Franke A, Lieb W, Thiele H, Altmüller J, Nürnberg P, Klaschik K, Ernst C, Ditsch N, Jessen F, Ramirez A, Wappenschmidt B, Engel C, Rhiem K, Meindl A, Schmutzler RK, Hahnen E|display-authors = 6 | title = Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer | journal = JAMA Oncology | volume = 3 | issue = 9 | pages = 1245–48 | date = September 2017 | pmid = 28033443 | pmc = 5824291 | doi = 10.1001/jamaoncol.2016.5592 }}{{cite journal | vauthors = Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, etal | title = The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer | journal = npj Breast Cancer | volume = 5 | issue = 38 | date = November 2019 | page = 38 | pmid = 31700994 | pmc = 6825205 | doi = 10.1038/s41523-019-0127-5 }} A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers.{{cite journal | vauthors = Kiiski JI, Pelttari LM, Khan S, Freysteinsdottir ES, Reynisdottir I, Hart SN, Shimelis H, Vilske S, Kallioniemi A, Schleutker J, Leminen A, Bützow R, Blomqvist C, Barkardottir RB, Couch FJ, Aittomäki K, Nevanlinna H | display-authors = 6 | title = Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 42 | pages = 15172–7 | date = October 2014 | pmid = 25288723 | pmc = 4210278 | doi = 10.1073/pnas.1407909111 | bibcode = 2014PNAS..11115172K | doi-access = free }} FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours{{cite journal | vauthors = Dicks E, Song H, Ramus SJ, Oudenhove EV, Tyrer JP, Intermaggio MP, Kar S, Harrington P, Bowtell DD, Group AS, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Piskorz A, Goranova T, Kent E, Siddiqui N, Paul J, Crawford R, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Sieh W, McGuire V, Lester J, Odunsi K, Whittemore AS, Bogdanova N, Dürst M, Hillemanns P, Karlan BY, Gentry-Maharaj A, Menon U, Tischkowitz M, Levine D, Brenton JD, Dörk T, Goode EL, Gayther SA, Pharoah DP | display-authors = 6 | title = FANCM as a likely high grade serous ovarian cancer susceptibility gene | journal = Oncotarget | volume = 8 | issue = 31 | pages = 50930–50940 | date = August 2017 | pmid = 28881617 | pmc = 5584218 | doi = 10.18632/oncotarget.15871 }}

Expression and activity of FANCM, is essential for the viability of cancers using Alternative Lengthening of Telomeres (ALT-associated cancers).{{cite journal | vauthors = Pan X, Drosopoulos WC, Sethi L, Madireddy A, Schildkraut CL, Zhang D | title = FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 29 | pages = E5940–E5949 | date = July 2017 | pmid = 28673972 | pmc = 5530707 | doi = 10.1073/pnas.1708065114 | bibcode = 2017PNAS..114E5940P | doi-access = free }}{{cite journal | vauthors = Lu R, O'Rourke JJ, Sobinoff AP, Allen JA, Nelson CB, Tomlinson CG, Lee M, Reddel RR, Deans AJ, Pickett HA | display-authors = 6 | title = The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT) | journal = Nature Communications | volume = 10 | issue = 1 | pages = 2252 | date = May 2019 | pmid = 31138797 | pmc = 6538672 | doi = 10.1038/s41467-019-10180-6 | bibcode = 2019NatCo..10.2252L }}{{cite journal | vauthors = Silva B, Pentz R, Figueira AM, Arora R, Lee YW, Hodson C, Wischnewski H, Deans AJ, Azzalin CM | display-authors = 6 | title = FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops | journal = Nature Communications | volume = 10 | issue = 1 | pages = 2253 | date = May 2019 | pmid = 31138795 | pmc = 6538666 | doi = 10.1038/s41467-019-10179-z | bibcode = 2019NatCo..10.2253S }} Several other synthetic lethal interactions have been observed for FANCM that may widen the targetability of the protein in therapeutic use.

There are several potential ways in which FANCM activity could be targeted as an anti-cancer agent. In the context of ALT, one of the best targets may be a peptide domain of FANCM called MM2. Ectopic MM2 peptide (that acts as a dominant decoy) was sufficient to inhibit colony formation of ALT-associated cancer cells, but not telomerase-positive cancer cells. This peptide works as a dominant interfering binder to RMI1:RMI2, and sequesters another DNA repair complex called the Bloom Syndrome complex away from FANCM. As with FANCM depletion, this induces death through a “hyper-ALT” phenotype. An in vitro high-throughput screen for small molecule inhibitors of MM2-RMI1:2 interaction lead to the discovery of PIP-199.{{cite journal | vauthors = Voter AF, Manthei KA, Keck JL | title = A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway | journal = Journal of Biomolecular Screening | volume = 21 | issue = 6 | pages = 626–33 | date = July 2016 | pmid = 26962873 | pmc = 5038921 | doi = 10.1177/1087057116635503 }} This experimental drug also showed some discriminatory activity in killing of ALT-cells, compared to telomerase-positive cells.

File:Homologous Recombination.jpg

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).

FANCM acts as a meiotic anti-crossover factor in mammals, limiting the number of crossovers during meiotic recombination. Deletion of the Fancm gene in mice leads to an increase in genome-wide crossover frequencies and perturbed gametogenesis, consistent with reproductive defects observed in humans with biallelic FANCM mutations.{{Cite journal |last=Tsui |first=Vanessa |last2=Lyu |first2=Ruqian |last3=Novakovic |first3=Stevan |last4=Stringer |first4=Jessica M. |last5=Dunleavy |first5=Jessica E.M. |last6=Granger |first6=Elissah |last7=Semple |first7=Tim |last8=Leichter |first8=Anna |last9=Martelotto |first9=Luciano G. |last10=Merriner |first10=D. Jo |last11=Liu |first11=Ruijie |last12=McNeill |first12=Lucy |last13=Zerafa |first13=Nadeen |last14=Hoffmann |first14=Eva R. |last15=O’Bryan |first15=Moira K. |date=2023 |title=Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals |url=https://linkinghub.elsevier.com/retrieve/pii/S2666979X23001246 |journal=Cell Genomics |language=en |volume=3 |issue=8 |pages=100349 |doi=10.1016/j.xgen.2023.100349 |pmc=10435384 |pmid=37601968}}

In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants.{{cite journal | vauthors = Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, Lemhemdi A, Macaisne N, Van Leene J, Gevaert K, De Jaeger G, Chelysheva L, Mercier R | display-authors = 6 | title = Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 15 | pages = 4713–8 | date = April 2015 | pmid = 25825745 | pmc = 4403193 | doi = 10.1073/pnas.1423107112 | bibcode = 2015PNAS..112.4713S | doi-access = free }} The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana.{{cite journal | vauthors = Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, Copenhaver GP, Horlow C, Mercier R | s2cid = 14570996 | display-authors = 6 | title = FANCM limits meiotic crossovers | journal = Science | volume = 336 | issue = 6088 | pages = 1588–90 | date = June 2012 | pmid = 22723424 | doi = 10.1126/science.1220381 | bibcode = 2012Sci...336.1588C }} A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination. 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; the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al. 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.{{cite journal | vauthors = Lorenz A, Osman F, Sun W, Nandi S, Steinacher R, Whitby MC | title = The fission yeast FANCM ortholog directs non-crossover recombination during meiosis | journal = Science | volume = 336 | issue = 6088 | pages = 1585–8 | date = June 2012 | pmid = 22723423 | pmc = 3399777 | doi = 10.1126/science.1220111 | bibcode = 2012Sci...336.1585L }}

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• {{MeshName|FANCM+protein,+human|3=FANCM protein, human}}

{{DNA repair}}

Category:Human proteins