Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M.
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.
Bakker
Sietske T
ST
Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
van de Vrugt
Henri J
HJ
Rooimans
Martin A
MA
Oostra
Anneke B
AB
Steltenpool
Jurgen
J
Delzenne-Goette
Elly
E
van der Wal
Anja
A
van der Valk
Martin
M
Joenje
Hans
H
te Riele
Hein
H
de Winter
Johan P
JP
D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000002:abnormalities / Q000378:metabolism; D010641:Phenotype; D012854:Sister Chromatid Exchange; D015996:Survival Rate; D013737:Testis / Q000002:abnormalities / Q000378:metabolism
D051856:Fanconi Anemia Complementation Group Proteins