LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
复制标题
DOI：
10.21203/rs.3.rs-275582/v1
复制
发表时间：
2021-03
期刊：
影响因子：
8.8
通讯作者：
Bing Zhang;Pengyi Yan;Zixuan Li;Jun-Ping Xiong;Zilong Geng;Weiting Wei;Yan Zhang;Gengze Wu;Zhuang Tao;Xiaoyu Tian;Zhijie Liu;Junling Liu;Kun Sun;Alex F Chen;Yu Zhang;C. Zeng;Yu Huang
中科院分区：
文献类型：
--
作者：
Bing Zhang;Pengyi Yan;Zixuan Li;Jun-Ping Xiong;Zilong Geng;Weiting Wei;Yan Zhang;Gengze Wu;Zhuang Tao;Xiaoyu Tian;Zhijie Liu;Junling Liu;Kun Sun;Alex F Chen;Yu Zhang;C. Zeng;Yu Huang
细胞衰老与多效性生理病理过程相关，包括衰老和年龄相关疾病。持续的 DNA 损伤是导致衰老的主要压力，但潜在的分子联系仍然难以捉摸。在这里，我们确定了 La 核糖核蛋白 7 (LARP7)（一种 7SK RNA 结合蛋白）作为衰老拮抗剂。 DNA 损伤介导的共济失调毛细血管扩张突变 (ATM) 激活会触发细胞外穿梭和 LARP7 下调，从而抑制 SIRT1 脱乙酰酶活性，通过增强 p53 和 NF-κB (p65) 的乙酰化来增强其转录活性，从而加速细胞衰老。在啮齿动物模型中，LARP7 的缺失会导致衰老细胞积累和过早衰老。此外，我们发现该 ATM-LARP7-SIRT1-p53/p65 衰老轴在血管衰老和动脉粥样硬化形成中具有活性，并且防止其激活可显着减轻衰老和动脉粥样硬化形成。总之，这项研究确定 LARP7 是衰老的看门人，并且改变的 ATM-LARP7-SIRT1-p53/p65 通路在 DNA 损伤反应 (DDR) 介导的细胞衰老和动脉粥样硬化中发挥重要作用。
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.