Fig. 9.

Model for replication stress and its aftermath in the absence of BRCA2. BRCA2 suppresses replication stress and DNA under replication in non-transformed cells primarily through RAD51-mediated HR repair of DNA damage. Protection of stalled replication forks from MRE11-mediated degradation plays a minor role. Upon BRCA2 deficiency, single-stranded DNA lesions accumulate in G2, generated, in part, by fork reversal (not shown) and hyper-resection. Unrepaired DNA damage perturbs the timely completion of DNA replication, leading to under replication. During early mitosis, the compensatory mitotic DNA synthesis pathway is insufficient, such that these unresolved DNA structures lead to anaphase abnormalities and formation of 53BP1 nuclear bodies in the next G1 phase. G1 arrest and cellular senescence mediated by p53 and p53-independent apoptosis are in turn triggered to ultimately result in cell inviability