FANCM

The protein encoded by this gene, FANCM displays DNA binding against fork structures 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. 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. ==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. Mono-allelic FANCM mutations are associated with breast cancer risk and especially with risk of developing ER-negative and TNBC disease subtypes. A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers. FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours ==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). Several other synthetic lethal interactions have been observed for FANCM that may widen the targetability of the protein in therapeutic use. This experimental drug also showed some discriminatory activity in killing of ALT-cells, compared to telomerase-positive cells. ==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). 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. In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants. The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana. A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination. == References ==