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
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).

In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants. [25] The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana. [26] A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination. [25] 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; [26] the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al. [25] 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. [27]

Related Research Articles

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

Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. 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), and 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.

<span class="mw-page-title-main">Helicase</span> Class of enzymes to unpack an organisms genes

Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.

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">Bloom syndrome</span> Medical condition

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family. Mutations in other members of this family, namely WRN and RECQL4, are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both and by cancer predisposition.

<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">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>

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>

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

<span class="mw-page-title-main">DNA repair and recombination protein RAD54-like</span>

DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L 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">FANCF</span>

Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.

<span class="mw-page-title-main">TOP3A</span>

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

<span class="mw-page-title-main">FANCL</span>

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

<span class="mw-page-title-main">SMC6</span>

Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.

<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.

Sgs1, also known as slow growth suppressor 1, is a DNA helicase protein found in Saccharomyces cerevisiae. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair. In particular, Sgs1 collaborates with other proteins to repair double-strand breaks during homologous recombination in eukaryotes.

<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.

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. 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. 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.
  26. 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.
  27. ↑ 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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