FANCM
   HOME

TheInfoList



OR:

Fanconi anemia, complementation group M, also known as FANCM is a human
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.


Function

The
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
encoded by this gene, FANCM displays DNA binding against fork structures and an
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
activity associated with DNA branch migration. It is believed that FANCM in conjunction with other
Fanconi anemia 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 nor ...
- proteins repair DNA at stalled
replication fork In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
s, and stalled transcription structures called
R-loop An R-loop is a three-stranded nucleic acid structure, composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA. R-loops may be formed in a variety of circumstances, and may be tolerated or cleared by cellular components. T ...
s. 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. 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 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 nor ...
, 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. 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 Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
-positive cancer cells. This peptide works as a dominant interfering binder to RMI1:RMI2, and sequesters another DNA repair complex called the
Bloom Syndrome Bloom syndrome (often abbreviated as BS in literature) 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'' gen ...
complex away from FANCM. 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. 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 A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
that is not broken forming a displacement loop (
D-loop In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this cas ...
). 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 Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...
and
Homologous recombination 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 (usually DNA as in cellular organisms but may ...
). 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. 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. 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; the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al. 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.


References


External links

* {{MeshName, FANCM+protein,+human, 3=FANCM protein, human