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FANCM
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFANCM, FAAP250, KIAA1596, Fanconi anemia complementation group M, FA complementation group M, POF15, SPGF28
External IDsOMIM: 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 MbChr 12: 65.12 – 65.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Fanconi anemia, complementation group M
Identifiers
SymbolFANCM
Alt. symbolsKIAA1596
NCBI gene57697
HGNC23168
OMIM609644
PDB4BXO
RefSeqXM_048128
UniProtQ8IYD8
Other data
EC number3.6.1.-
LocusChr. 14 q21.3
Search for
StructuresSwiss-model
DomainsInterPro

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]

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.

FANCM crystal structures
Mechanism by which FANCM interacts with DNA, determined by protein crystallography of DNA bound protein fragments[9][12]

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.

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]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000187790 – Ensembl, May 2017
  2. ^ a b c 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.
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  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.
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source: https://en.wikipedia.org/wiki/FANCM

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