LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity
Pengyi Yan, Zixuan Li, Junhao Xiong, Zilong Geng, Weiting Wei, Yan Zhang, Gengze Wu, Tao Zhuang, Xiaoyu Tian, Zhijie Liu, Junling Liu, Kun Sun, Fengyuan Chen, Yuzhen Zhang, Chunyu Zeng, Yu Huang, Bing Zhang
Journal：Cell Reports
IF：9.42
DOI：10.1016/j.celrep.2021.110038
PMID：34818543
Published：2021-11-23
research field：分子生物学细胞生物学衰老研究病理学
Abstract
Summary Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
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