FANCM
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Fanconi anemia, complementation group M | |||||||
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Identifiers | |||||||
Symbol | FANCM | ||||||
Alt. symbols | KIAA1596 | ||||||
Chr. 14 q21.3 | |||||||
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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
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.
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
Meiosis
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]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000187790 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055884 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 10997877.
- PMID 16116422.
- PMID 29209649.
- ^ PMID 31663812.
- ^ PMID 23932590.
- PMID 18206976.
- ^ PMID 20064461.
- PMID 24773018.
- PMID 12724401.
- S2CID 4707069.
- PMID 28837162.
- PMID 26130695.
- PMID 28033443.
- PMID 31700994.
- PMID 25288723.
- PMID 28881617.
- ^ PMID 28673972.
- ^ PMID 31138797.
- PMID 31138795.
- PMID 26962873.
- ^ PMID 25825745.
- ^ S2CID 14570996.
- PMID 22723423.
External links
- FANCM protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)