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

Producción científica: Articlerevisión exhaustiva

38 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Número de artículo110038
PublicaciónCell Reports
Volumen37
N.º8
DOI
EstadoPublished - nov 23 2021

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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