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Human Molecular Genetics Advance Access originally published online on June 26, 2009
Human Molecular Genetics 2009 18(18):3484-3495; doi:10.1093/hmg/ddp297
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Sietske T. Bakker1,2, Henri J. van de Vrugt2, Martin A. Rooimans2, Anneke B. Oostra2, Jurgen Steltenpool2, Elly Delzenne-Goette1, Anja van der Wal1, Martin van der Valk1, Hans Joenje2, Hein te Riele1,* and Johan P. de Winter2,*

1 Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, NL-1066 CX Amsterdam, The Netherlands and 2 Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands

* To whom correspondence should be addressed. Tel: +31 205122084; Fax: +31 206691383; Email: h.t.riele{at}nki.nl (H.R.); Tel: +31 204448423; Fax: +31 204448285; Email: j.dewinter{at}vumc.nl (J.P.W.)

Received March 20, 2009; Accepted June 24, 2009

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{Delta}2/{Delta}2 mice also showed unique features atypical for FA mice, including underrepresentation of female Fancm{Delta}2/{Delta}2 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.


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