Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Significance Mutant form of p53 (mutp53) proteins are expressed at high levels in many human cancers and can promote tumor cell growth. However, their mechanisms of action have not been fully understood. Elucidation of the mechanisms may identify new therapeutic strategies for treating many cancers that contain mutp53s. We describe a role for several hotspot mutp53s in reducing the checkpoint response to replication stress through interacting with TopBP1. This finding provides a rationale for a synthetic lethality strategy to treat mutp53-harboring cancer cells with inhibitors of another ATR activator, DNA2. We also find that certain mutp53s directly promote DNA replication by bridging the interaction between TopBP1 and Treslin. These results uncover mechanisms by which mutp53 enhances DNA replication.