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

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. Victorelli, Seung-Hwa Woo, Anthony B. Lagnado, Michael A. LaPorta, Tianhui Liu, Nirmalya Dasgupta, Sha Li, Andrew Davis, Anatoly Korotkov, Erik Hultenius, Zichen Gao, Yoav Altman, Rebecca A. Porritt, Guillermina Garcia, Carolin Mogler, Andrei Seluanov, Vera Gorbunova, Susan M. Kaech, Xiao Tian, Zhixun Dou, Chongyi Chen, João F. Passos and Peter D. Adams ()
Additional contact information
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
Seung-Hwa Woo: Department of Physiology and Biomedical Engineering; Mayo Clinic
Anthony B. Lagnado: Department of Physiology and Biomedical Engineering; 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
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
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
Peter D. Adams: Cancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57229-3

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