Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance.

摘要: We have previously reported that p53 decelerates nascent DNA elongation in complex with the translesion synthesis (TLS) polymerase ι (POLι) which triggers a homology-directed damage tolerance (DDT) pathway to bypass obstacles during replication. Here, we demonstrate this DDT relies on multiple activities, can be disrupted by TP53 mutations including those frequently found cancer tissues. show p53-mediated depends its oligomerization domain (OD), while regulatory C-terminus is not involved. Mutation of residues S315 and D48/D49, abrogate interactions repair replication proteins topoisomerase I RPA, respectively, L22/W23, disrupt formation p53-POLι complexes, all prevent pathway. Our results requires binding-proficient tetramer, recruitment such tetramer RPA-coated forks POLι. Importantly, our mutational analysis demonstrates transcriptional transactivation dispensable for POLι-mediated pathway, protects against from endogenous exogenous sources.