Language
English
Publication Date
11-5-2025
Journal
Communications Biology
DOI
10.1038/s42003-025-09050-3
PMID
41193733
PMCID
PMC12589595
PubMedCentral® Posted Date
11-5-2025
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Tumor Suppressor Protein p53, Humans, Nucleotidyltransferases, Animals, Membrane Proteins, Mice, Immune Checkpoint Inhibitors, Mutation, Cell Line, Tumor, Female, DNA Replication, Carrier Proteins, DNA-Binding Proteins, Nuclear Proteins
Published Open-Access
yes
Recommended Citation
Liu, Kang; Garan, Lidija A Wilhelms; Lin, Fang-Tsyr; et al., "Mutant p53 Variants Differentially Impact Replication Initiation and Activate cGAS-Sting To Affect Immune Checkpoint Inhibition" (2025). Faculty and Staff Publications. 4634.
https://digitalcommons.library.tmc.edu/baylor_docs/4634