Nature communications · 2025
p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
СтатьяНазвание и аннотация: Перевод в очереди
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Miller Karl N, Li Brightany, Pierce-Hoffman Hannah R, Patel Shreeya, Lei Xue, Rajesh Adarsh, Teneche Marcos G, Havas Aaron P, Gandhi Armin, Macip Carolina Cano, Lyu Jun, Victorelli Stella G, Woo Seung-Hwa, Lagnado Anthony B, LaPorta Michael A, Liu Tianhui, Dasgupta Nirmalya, Li Sha, Davis Andrew, Korotkov Anatoly, Hultenius Erik, Gao Zichen, Altman Yoav, Porritt Rebecca A, Garcia Guillermina, Mogler Carolin, Seluanov Andrei, Gorbunova Vera, Kaech Susan M, Tian Xiao, Dou Zhixun, Chen Chongyi, Passos João F, Adams Peter D
Аннотация
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.