Research Interests

Significance of the Fanconi anemia pathway in cancer

Sietske Bakker
(Graduate student)
Elly Delzenne-Goette
(Technical staff)

Fanconi anemia (FA) is a recessive disease characterized by malformations, progressive anemia and predisposition to cancer. Thus far, 14 genes have been implicated in FA. At the cellular level, loss of any of these genes leads to high sensitivity to DNA crosslinking agents as manifested by G2 arrest, chromosomal aberrations and cell killing. In collaboration with the group of Hans Joenje and Johan de Winter at the VU University Medical Center Amsterdam, we are studying the consequences of genetic defects in the FA pathway for the etiology and behavior of tumors. To this aim we have generated several novel mouse models for Fanconi anemia.

We found that Fancm deficiency caused hypogonadism in mice and hypersensitivity to cross-linking agents in mouse embryonic fibroblasts (MEFs), thus phenocopying other FA mouse models (Bakker et al., 2009). However, Fancm knockout mice also showed unique features atypical for FA mice, including underrepresentation of female mice and decreased overall and tumor-free survival. Increased cancer incidence may be correlated to the role of FANCM in the suppression of spontaneous sister chromatid exchanges that we observed in MEFs. In addition, FANCM appeared to have a stimulatory rather than essential role in FANCD2 monoubiquitination. The FA-M mouse model suggests that FANCM functions both inside and outside the FA core complex to maintain genome stability and to prevent tumorigenesis.