p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells
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.
Article Details
Authors (34)
Karl N. Miller
Brightany Li
Hannah R. Pierce-Hoffman
Shreeya Patel
Xue Lei
Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute
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
School of Sciences, Great Bay University 1 , Dongguan 523000,
Nirmalya Dasgupta
Sha Li
State Key Laboratory of Palaeobiology and Stratigraphy, Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences
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