RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair

Authors

  • Jingxin Wang,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Naduparambil K Jacob,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Katherine J Ladner,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Amer Beg,

    1. Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute at USF, Tampa, Florida, USA
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  • James D Perko,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Stephan M Tanner,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Sandya Liyanarachchi,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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  • Richard Fishel,

    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    3. Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Denis C Guttridge

    Corresponding author
    1. Human Cancer Genetics Program, and Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    3. Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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Abstract

Nuclear factor (NF)-κB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF-κB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65−/− murine fibroblasts immortalize at considerably faster rates than RelA/p65+/+ cells. The ability of RelA/p65−/− fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65−/− fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF-κB. Altogether, our findings present a fresh perspective on the role of NF-κB as a tumour suppressor, which acts in pre-neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability.

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