Absence of Brca2 causes genome instability by chromosome breakage and lossassociated with centrosome amplification

Women heterozygous for mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2 have a highly elevated risk of developing breast cancer [1] . BRCA1 and BRCA2 encode large proteins with no sequence similarity to one another. Although involvement in DNA repair and transcription has been sugg ested, it is still not understood how loss of function of these genes leads to breast cancer [2]. Embryonic fibroblasts (MEFs) derived from mice homoz ygous for a hypomorphic mutation (Brca2(Tr2014)) within the 3' region of ex on 11 in Brca2 [3], or a similar mutation (Brca2(Tr)) [4], proliferate poor ly in culture and overexpress the tumour suppressor p53 and the cyclin-depe ndent kinase inhibitor p21(Waf1/Cip1). These MEFs have intact p53-dependent DNA damage G(1)-S [3,4] and G(2)-M checkpoints [4], but are impaired in DN A double-strand break repair [3] and develop chromosome aberrations [4]. He re, we report that Brca2(Tr2014/Tr2014) MEFs frequently develop micronuclei . These abnormal DNA-containing bodies were formed through both loss of ace ntric chromosome fragments and by chromosome missegregation, which resulted in aneuploidy. Absence of Brca2 also led to centrosome amplification, whic h we found associated with the formation of micronuclei, These data suggest a potential mechanism whereby loss of BRCA2 may, within subclones, drive t he loss of cell-cycle regulation genes, enabling proliferation and tumourig enesis.