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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • 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,
  • Peter D. Adams

摘要

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.