Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.
Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China.
Cell Rep. 2021 Nov 23;37(8):110038. doi: 10.1016/j.celrep.2021.110038.
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.
细胞衰老与多种生理病理过程有关，包括衰老和与年龄相关的疾病。持续的 DNA 损伤是导致衰老的主要应激源，但潜在的分子联系仍不清楚。在这里，我们发现 La 核糖核蛋白 7（LARP7），一种 7SK RNA 结合蛋白，是一种衰老拮抗物。DNA 损伤介导的共济失调毛细血管扩张突变（ATM）激活触发 LARP7 的细胞外穿梭和下调，这抑制了 SIRT1 去乙酰化酶活性，通过增强它们的乙酰化来增强 p53 和 NF-κB（p65）转录活性，从而加速细胞衰老。LARP7 的缺失导致啮齿动物模型中衰老细胞的积累和早衰。此外，我们表明，ATM-LARP7-SIRT1-p53/p65 衰老轴在血管衰老和动脉粥样硬化形成中活跃，并且阻止其激活可显著减轻衰老和动脉粥样硬化形成。总之，这项研究确定了 LARP7 是衰老的守门员，改变的 ATM-LARP7-SIRT1-p53/p65 途径在 DDR 介导的细胞衰老和动脉粥样硬化形成中起重要作用。
