Mutant p53 Gains Oncogenic Functions Through a Chromosomal Instability-Induced Cytosolic DNA Response

Authors

Mei Zhao
Tianxiao Wang
Frederico O Gleber-Netto
Zhen Chen
Daniel J McGrail
Javier A Gomez
Wutong Ju
Mayur A Gadhikar
Wencai Ma
Li Shen
Qi Wang
Ximing Tang
Sen Pathak
Maria Gabriela Raso
Jared K Burks
Shiaw-Yih Lin
Jing Wang
Asha S Multani
Curtis R Pickering
Junjie Chen
Jeffrey N Myers
Ge Zhou

Publication Date

1-2-2024

Journal

Nature Communications

Abstract

Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.

Keywords

Humans, Tumor Suppressor Protein p53, NF-kappa B, Neoplasms, DNA, Chromosomal Instability, Nucleotidyltransferases, Interferons, Tumor Microenvironment

Comments

Supplementary Materials

Data Availability Statement

PMID: 38167338