Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response

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 () and Ge Zhou ()
Additional contact information
Mei Zhao: The University of Texas MD Anderson Cancer Center
Tianxiao Wang: The University of Texas MD Anderson Cancer Center
Frederico O. Gleber-Netto: The University of Texas MD Anderson Cancer Center
Zhen Chen: The University of Texas MD Anderson Cancer Center
Daniel J. McGrail: The University of Texas MD Anderson Cancer Center
Javier A. Gomez: The University of Texas MD Anderson Cancer Center
Wutong Ju: The University of Texas MD Anderson Cancer Center
Mayur A. Gadhikar: The University of Texas MD Anderson Cancer Center
Wencai Ma: The University of Texas MD Anderson Cancer Center
Li Shen: The University of Texas MD Anderson Cancer Center
Qi Wang: The University of Texas MD Anderson Cancer Center
Ximing Tang: The University of Texas MD Anderson Cancer Center
Sen Pathak: The University of Texas MD Anderson Cancer Center
Maria Gabriela Raso: The University of Texas MD Anderson Cancer Center
Jared K. Burks: The University of Texas MD Anderson Cancer Center
Shiaw-Yih Lin: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Asha S. Multani: The University of Texas MD Anderson Cancer Center
Curtis R. Pickering: The University of Texas MD Anderson Cancer Center
Junjie Chen: The University of Texas MD Anderson Cancer Center
Jeffrey N. Myers: The University of Texas MD Anderson Cancer Center
Ge Zhou: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44239-2

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