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p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells

Author

Listed:
  • Karl N. Miller

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Brightany Li

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Hannah R. Pierce-Hoffman

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Shreeya Patel

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Xue Lei

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Adarsh Rajesh

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Marcos G. Teneche

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Aaron P. Havas

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Armin Gandhi

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Carolina Cano Macip

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Jun Lyu

    (Laboratory of Biochemistry and Molecular Biology; National Cancer Institute; National Institutes of Health)

  • Stella G. Victorelli

    (Department of Physiology and Biomedical Engineering; Mayo Clinic
    Robert and Arlene Kogod Center on Aging; Mayo Clinic)

  • Seung-Hwa Woo

    (Department of Physiology and Biomedical Engineering; Mayo Clinic
    Robert and Arlene Kogod Center on Aging; Mayo Clinic)

  • Anthony B. Lagnado

    (Department of Physiology and Biomedical Engineering; Mayo Clinic
    Robert and Arlene Kogod Center on Aging; Mayo Clinic)

  • Michael A. LaPorta

    (NOMIS Center for Immunobiology and Microbial Pathogenesis; Salk Institute for Biological Studies)

  • Tianhui Liu

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Nirmalya Dasgupta

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI
    Center for Cancer Therapy; La Jolla Institute of Immunology)

  • Sha Li

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Andrew Davis

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Anatoly Korotkov

    (Departments of Biology and Medicine; University of Rochester)

  • Erik Hultenius

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Zichen Gao

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Yoav Altman

    (Shared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI)

  • Rebecca A. Porritt

    (Shared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI)

  • Guillermina Garcia

    (Shared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI)

  • Carolin Mogler

    (Institute of Pathology; School of Medicine and Health; Technical University Munich (TUM))

  • Andrei Seluanov

    (Departments of Biology and Medicine; University of Rochester)

  • Vera Gorbunova

    (Departments of Biology and Medicine; University of Rochester)

  • Susan M. Kaech

    (NOMIS Center for Immunobiology and Microbial Pathogenesis; Salk Institute for Biological Studies)

  • Xiao Tian

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

  • Zhixun Dou

    (Department of Medicine; Massachusetts General Research Institute
    Harvard Stem Cell Institute; Harvard University)

  • Chongyi Chen

    (Laboratory of Biochemistry and Molecular Biology; National Cancer Institute; National Institutes of Health)

  • João F. Passos

    (Department of Physiology and Biomedical Engineering; Mayo Clinic
    Robert and Arlene Kogod Center on Aging; Mayo Clinic)

  • Peter D. Adams

    (Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI)

Abstract

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

Suggested Citation

  • Karl N. Miller & Brightany Li & Hannah R. Pierce-Hoffman & Shreeya Patel & Xue Lei & Adarsh Rajesh & Marcos G. Teneche & Aaron P. Havas & Armin Gandhi & Carolina Cano Macip & Jun Lyu & Stella G. Victo, 2025. "p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57229-3
    DOI: 10.1038/s41467-025-57229-3
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