Fanconi anemia, complementation group M, also known asFANCM is a humangene.[5][6] It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.[7][8]
Theprotein encoded by this gene, FANCM displays DNA binding against fork structures[9] and anATPase activity associated with DNA branch migration. It is believed that FANCM in conjunction with otherFanconi anemia- proteins repairDNA at stalledreplication forks, and stalled transcription structures calledR-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[9][12]
Bi-allelic mutations in the FANCM gene were originally associated withFanconi 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]
Expression and activity of FANCM, is essential for the viability of cancers usingAlternative 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 nottelomerase-positive cancer cells.[22] This peptide works as a dominant interfering binder to RMI1:RMI2, and sequesters another DNA repair complex called theBloom Syndrome complex away from FANCM.[11] As with FANCM depletion, this induces death through a “hyper-ALT” phenotype. Anin 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]
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 ahomologous chromosome that is not broken forming adisplacement 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 (seeGenetic recombination andHomologous 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 plantArabidopsis 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 inA. 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 inA. 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 yeastSchizosaccharomyces pombe, FANCM helicase also directs NCO recombination during meiosis.[28]
^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.PMID24773018.
