Fig. 8

Proposed model depicting how p53-independent p21^WAF1/Cip1 expression fuels Rad52-dependent error-prone double strand break repair promoting genomic instability. Sustained p53-independent p21^WAF1/Cip1 induction leads to increased levels of nucleotide lesions mediated by elevated reactive oxygen species (ROS). Given the negative impact exerted by p21^WAF1/Cip1 on the error free nucleotide repair mechanisms (BER and NER), a significant proportion of such base lesions escape unrepaired. This creates an additional repair “load” to the error prone repair mechanism of TLS, which is further compromised by p21^WAF1/Cip1 overexpression, leading to a decreased SNS load and in favor of DSBs. In turn, this further increases the DSB burden generated also through re-replication [9]. As components of SDSA are down-regulated, a shift to Rad52-mediated error prone DNA repair takes place by invoking the BIR and SSA repair routes, fueling genomic instability. This repair switch is mediated by a shift in the balance between Rad51 and Rad52 levels as the former is suppressed by E2F4 [9] and the latter is induced by E2F1 (present study). DSB DNA double strand break, BER base excision repair, NER nucleotide excision repair, TLS translesion DNA synthesis and repair, SDSA synthesis-dependent strand annealing, BIR break-induced repair, SSA single strand annealing