FANCM

Last updated
FANCM
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FANCM , FAAP250, KIAA1596, Fanconi anemia complementation group M, FA complementation group M, POF15, SPGF28
External IDs OMIM: 609644; MGI: 2442306; HomoloGene: 35378; GeneCards: FANCM; OMA:FANCM - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57697

104806

Ensembl

ENSG00000187790

ENSMUSG00000055884

UniProt

Q8IYD8

Q8BGE5

RefSeq (mRNA)

NM_001308133
NM_001308134
NM_020937

NM_178912
NM_001364447

RefSeq (protein)

NP_001295062
NP_001295063
NP_065988

NP_849243
NP_001351376

Location (UCSC) Chr 14: 45.14 – 45.2 Mb Chr 12: 65.12 – 65.18 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Fanconi anemia, complementation group M
Identifiers
SymbolFANCM
Alt. symbolsKIAA1596
NCBI gene 57697
HGNC 23168
OMIM 609644
PDB 4BXO
RefSeq XM_048128
UniProt Q8IYD8
Other data
EC number 3.6.1.-
Locus Chr. 14 q21.3
Search for
Structures Swiss-model
Domains InterPro

Fanconi anemia, complementation group M, also known as FANCM is a human gene. [5] [6] It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies. [7] [8]

Contents

Function

The protein encoded by this gene, FANCM displays DNA binding against fork structures [9] 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. [10] [11]

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. [9] 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.

Mechanism by which FANCM interacts with DNA, determined by protein crystallography of DNA bound protein fragments FANCM structures sml.jpg
Mechanism by which FANCM interacts with DNA, determined by protein crystallography of DNA bound protein fragments

Disease association

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. [13] [14] [15] Mono-allelic FANCM mutations are associated with breast cancer risk and especially with risk of developing ER-negative and TNBC disease subtypes. [16] [17] [18] A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers. [19] FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours [20]

FANCM as a therapeutic target in ALT cancer

Expression and activity of FANCM, is essential for the viability of cancers using Alternative Lengthening of Telomeres (ALT-associated cancers). [21] [22] [23] Several other synthetic lethal interactions have been observed for FANCM that may widen the targetability of the protein in therapeutic use. [21] [8]

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. [22] 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. [11] 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. [24] This experimental drug also showed some discriminatory activity in killing of ALT-cells, compared to telomerase-positive cells. [22]

Meiosis

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. Homologous Recombination.jpg
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).

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 [25] .

In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants. [26] The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana. [27] A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination. [26] 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; [27] the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al. [26] 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. [28]

Related Research Articles

<span class="mw-page-title-main">Chromosomal crossover</span> Cellular process

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

<span class="mw-page-title-main">Bloom syndrome protein</span> Mammalian protein found in humans

Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.

<span class="mw-page-title-main">Fanconi anemia, complementation group C</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group C protein is a protein that in humans is encoded by the FANCC gene. This protein delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. Mutations in this gene result in Fanconi anemia, a human rare disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages.

<span class="mw-page-title-main">FANCA</span> Protein-coding gene in the species Homo sapiens

Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.

<span class="mw-page-title-main">FANCD2</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN and FANCO.

<span class="mw-page-title-main">FANCG</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.

<span class="mw-page-title-main">Exonuclease 1</span> Protein-coding gene in the species Homo sapiens

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.

<span class="mw-page-title-main">BRIP1</span> Mammalian protein found in Homo sapiens

Fanconi anemia group J protein is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene.

<span class="mw-page-title-main">TOP3A</span> Protein-coding gene in the species Homo sapiens

DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.

<span class="mw-page-title-main">FANCL</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

<span class="mw-page-title-main">FANCI</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia, complementation group I (FANCI) also known as KIAA1794, is a protein which in humans is encoded by the FANCI gene. Mutations in the FANCI gene are known to cause Fanconi anemia.

<span class="mw-page-title-main">PALB2</span> Protein-coding gene in the species Homo sapiens

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

<span class="mw-page-title-main">RMI1</span> Protein-coding gene in the species Homo sapiens

RecQ-mediated genome instability protein 1 is a protein that in humans is encoded by the RMI1 gene.

FANC proteins are a network of at least 15 proteins that are associated with a cell process known as the Fanconi anemia.

<span class="mw-page-title-main">Synthesis-dependent strand annealing</span>

Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000187790 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000055884 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Pan X, Ahmed N, Kong J, Zhang D (2017-11-02). "Breaking the end: Target the replication stress response at the ALT telomeres for cancer therapy". Molecular & Cellular Oncology. 4 (6): e1360978. doi:10.1080/23723556.2017.1360978. PMC   5706943 . PMID   29209649.
  8. 1 2 O'Rourke JJ, Bythell-Douglas R, Dunn EA, Deans AJ (October 2019). "ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres". Nucleus. 10 (1): 221–230. doi: 10.1080/19491034.2019.1685246 . PMC   6949022 . PMID   31663812.
  9. 1 2 3 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.
  10. ↑ 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.
  11. 1 2 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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. S2CID   4707069.
  15. ↑ 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" (PDF). Genetics in Medicine. 20 (4): 452–457. doi: 10.1038/gim.2017.123 . PMID   28837162.
  16. ↑ Peterlongo P, Catucci I, Colombo M, Caleca L, Mucaki E, Bogliolo M, et al. (September 2015). "FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor". Human Molecular Genetics. 24 (18): 5345–55. doi:10.1093/hmg/ddv251. PMC   4550823 . PMID   26130695.
  17. ↑ Neidhardt G, Hauke J, Ramser J, Groß E, Gehrig A, Müller CR, et al. (September 2017). "Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer". JAMA Oncology. 3 (9): 1245–48. doi:10.1001/jamaoncol.2016.5592. PMC   5824291 . PMID   28033443.
  18. ↑ Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, et al. (November 2019). "The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer". npj Breast Cancer. 5 (38): 38. doi:10.1038/s41523-019-0127-5. PMC   6825205 . PMID   31700994.
  19. ↑ 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. Bibcode:2014PNAS..11115172K. doi: 10.1073/pnas.1407909111 . PMC   4210278 . PMID   25288723.
  20. ↑ 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.
  21. 1 2 Pan X, Drosopoulos WC, Sethi L, Madireddy A, Schildkraut CL, Zhang D (July 2017). "FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres". Proceedings of the National Academy of Sciences of the United States of America. 114 (29): E5940–E5949. Bibcode:2017PNAS..114E5940P. doi: 10.1073/pnas.1708065114 . PMC   5530707 . PMID   28673972.
  22. 1 2 3 Lu R, O'Rourke JJ, Sobinoff AP, Allen JA, Nelson CB, Tomlinson CG, et al. (May 2019). "The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT)". Nature Communications. 10 (1): 2252. Bibcode:2019NatCo..10.2252L. doi:10.1038/s41467-019-10180-6. PMC   6538672 . PMID   31138797.
  23. ↑ Silva B, Pentz R, Figueira AM, Arora R, Lee YW, Hodson C, et al. (May 2019). "FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops". Nature Communications. 10 (1): 2253. Bibcode:2019NatCo..10.2253S. doi:10.1038/s41467-019-10179-z. PMC   6538666 . PMID   31138795.
  24. ↑ Voter AF, Manthei KA, Keck JL (July 2016). "A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway". Journal of Biomolecular Screening. 21 (6): 626–33. doi:10.1177/1087057116635503. PMC   5038921 . PMID   26962873.
  25. ↑ Tsui, Vanessa; Lyu, Ruqian; Novakovic, Stevan; Stringer, Jessica M.; Dunleavy, Jessica E.M.; Granger, Elissah; Semple, Tim; Leichter, Anna; Martelotto, Luciano G.; Merriner, D. Jo; Liu, Ruijie; McNeill, Lucy; Zerafa, Nadeen; Hoffmann, Eva R.; O’Bryan, Moira K. (2023). "Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals". Cell Genomics. 3 (8): 100349. doi:10.1016/j.xgen.2023.100349. PMC   10435384 . PMID   37601968.
  26. 1 2 3 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. Bibcode:2015PNAS..112.4713S. doi: 10.1073/pnas.1423107112 . PMC   4403193 . PMID   25825745.
  27. 1 2 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. Bibcode:2012Sci...336.1588C. doi:10.1126/science.1220381. PMID   22723424. S2CID   14570996.
  28. ↑ 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. Bibcode:2012Sci...336.1585L. doi:10.1126/science.1220111. PMC   3399777 . PMID   22723423.
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