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

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• Akt-dependent phosphorylation of TopBP1 normally switches Treslin binding to E2F1 binding, preventing DNA replication re-initiation in late S and G2 phases.
• TopBP1/Treslin interaction is crucial for cell cycle regulation and preventing genomic instability.

Purpose of the Study:

• To investigate the role of contact mutant p53 in overriding the TopBP1/Treslin to TopBP1/E2F1 binding switch.
• To explore the therapeutic implications of contact mutant p53-mediated replication stress in cancer.

Main Methods:

• Utilized binding assays and cell-based experiments to study protein interactions and DNA replication.
• Assessed micronuclei formation and sensitivity to various inhibitors in cancer cells.
• Investigated the activation of the cGAS-STING pathway and response to immune checkpoint inhibition.
• Validated findings in murine tumor models and analyzed clinical data.

Main Results:

• Contact mutant p53, but not conformational mutant p53, binds TopBP1 and Treslin, maintaining TopBP1/Treslin interaction in late S/G2 phases.
• This persistent interaction leads to replication over-firing, increased micronuclei formation, and heightened sensitivity to TopBP1-BRCT7/8, PARP, and ATR inhibitors.
• Contact mutant p53 induces MRE11 expression, activating the cGAS-STING pathway and enhancing responses to immune checkpoint inhibition.
• Findings were confirmed in preclinical models and clinical data.

Conclusions:

• Contact mutant p53 disrupts normal cell cycle control by preventing the TopBP1 binding switch, leading to replication stress.
• Targeting TopBP1 in combination with PARP or ATR inhibitors shows promise for treating cancers with contact mutant p53.
• Contact mutant p53-induced genomic instability and immune pathway activation offer new avenues for cancer immunotherapy.