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

Author

Listed:
  • Mei Zhao

    (The University of Texas MD Anderson Cancer Center)

  • Tianxiao Wang

    (The University of Texas MD Anderson Cancer Center
    Peking University Cancer Hospital & Institute)

  • 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
    Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic
    Lerner Research Institute, Cleveland Clinic)

  • 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
    Yale School of Medicine)

  • 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)

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.

Suggested Citation

  • 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 & Mari, 2024. "Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44239-2
    DOI: 10.1038/s41467-023-44239-2
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