Mutant p53 variants differentially impact replication initiation and activate cGAS-STING to affect immune checkpoint inhibition

Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity of cancer cells to a TopBP1-BRCT7/8 inhibitor combined with PARP or ATR inhibitors. Importantly, contact mutant p53 induces micronuclei formation and MRE11 expression, thereby activating cGAS-STING pathway and enhancing response to immune checkpoint inhibition. This finding is validated in murine mammary tumor allografts and further corroborated by clinical data.