Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M

Abstract

The Fanconi anemia (FA) core complex member FANCM remodels synthetic replication forks and recombination intermediates. Thus far, only one FA patient with FANCM mutations has been described, but the relevance of these mutations for the FA phenotype is uncertain. To provide further experimental access to the FA-M complementation group we have generated Fancm-deficient mice by deleting exon 2. FANCM deficiency caused hypogonadism in mice and hypersensitivity to cross-linking agents in mouse embryonic fibroblasts (MEFs), thus phenocopying other FA mouse models. However, Fancm(Delta2/Delta2) mice also showed unique features atypical for FA mice, including underrepresentation of female Fancm(Delta2/Delta2) mice and decreased overall and tumor-free survival. This increased cancer incidence may be correlated to the role of FANCM in the suppression of spontaneous sister chromatid exchanges as observed in MEFs. In addition, FANCM appeared to have a stimulatory rather than essential role in FANCD2 monoubiquitination. The FA-M mouse model presented here suggests that FANCM functions both inside and outside the FA core complex to maintain genome stability and to prevent tumorigenesis.

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

“…Our findings are consistent with previous studies showing that fancm-deficient mice have increased cancer incidence (33). In addition, homozygous missense mutations in FANCM (c.5164C>T, p.P1722S) have been found in breast tumors (35), and four different FANCM SNPs have been associated with osteosarcoma risk (36).…”

“…Also, in colorectal cancer (CRC) patients, an FANCM nonsense mutation (c.5791C>T, p.Arg1931Ter) has been identified (37), but further studies are needed to clarify the potential role of FANCM in CRC susceptibility. However, only one FA patient has been found to carry truncating FANCM mutation and this individual also carries biallelic mutations in the FANCA gene (33,38). Furthermore, homozygous carriers of FANCM loss-of-function mutations c.5101C>T and c.5791C>T observed in the Finnish population do not show symptoms of FA (39).…”

“…The two translocase domains in FANCM protein are located in the N terminus. It is likely that all these protein domains in FANCM act sequentially in replication fork processing (31,33,34) (Interpro; www.ebi.ac.uk/ interpro/protein/Q8IYD8; July 2014).…”

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

“…In fact, all FA mouse models to date exhibit the same fertility defect [18][19][20][21][22][23][24][25][26][27]. FA mutant mice are born with extremely few germ cells in either the testis or the ovary.…”

“…In other monozygotic twins with different phenotypes somatic mosacism was not detected. Additionally, in mouse models of Fanconi anaemia, in which somatic mosacism is not possible by virtue of both alleles carrying identical deletions, there is also a variable penetrance of the phenotype [18][19][20][21][22][23][24][25][26][27]. Hence, there is a stochastic element that contributes to the severity of the phenotype that is likely to be due to an endogenous or exogenous source of DNA damage.…”