ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels

下调和上调 衰老 阿达尔 细胞生物学 生物 核糖核酸 RNA编辑 RNA结合蛋白 信使核糖核酸 自噬 神经退行性变 分子生物学 遗传学 基因 内科学 细胞凋亡 医学 疾病
作者
Xue Hou,Yusuke Shiromoto,Masayuki Sakurai,Martina Towers,Qiang Zhang,Shuai Wu,Aaron Havas,Lu Wang,Shelley L. Berger,Peter D. Adams,Bin Tian,Kazuko Nishikura,Andrew V. Kossenkov,Pingyu Liu,Rugang Zhang
出处
期刊:Nature Cell Biology [Springer Nature]
卷期号:24 (8): 1202-1210 被引量:17
标识
DOI:10.1038/s41556-022-00959-z
摘要

Cellular senescence plays a causal role in ageing and, in mice, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders1,2. Adenosine deaminases acting on RNA (ADARs) are RNA-editing enzymes that are also implicated as important regulators of human ageing, and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms3,4. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through p16INK4a upregulation. The ADAR1 downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a-dependent and independent of its RNA-editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA-binding protein that increases the half-life and steady-state levels of its target mRNAs. SIRT1 in turn antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4a upregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing-independent role for ADAR1 in the regulation of senescence by post-transcriptionally controlling p16INK4a expression. Hao et al. describe an RNA-editing-independent role for ADAR1 in driving senescence. Autophagy downregulates ADAR1 in aged tissues, decreasing the binding of ADAR1 partner HuR to target mRNAs, including SIRT1. Loss of SIRT1 enhances p16INK4a levels.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
慕青应助Sayhai采纳,获得10
刚刚
1秒前
细腻幻雪发布了新的文献求助10
1秒前
Leonardi应助干净寄文采纳,获得20
1秒前
寻道图强应助科研通管家采纳,获得30
2秒前
Ava应助科研通管家采纳,获得10
2秒前
斯文败类应助科研通管家采纳,获得10
2秒前
今后应助科研通管家采纳,获得30
2秒前
深情安青应助科研通管家采纳,获得10
2秒前
2秒前
安安完成签到,获得积分10
2秒前
正直松鼠完成签到,获得积分10
2秒前
3秒前
3秒前
3秒前
酸化土壤改良应助Mia采纳,获得30
4秒前
4秒前
阿龙发布了新的文献求助10
4秒前
人群是那么像羊群完成签到,获得积分10
5秒前
安安发布了新的文献求助10
6秒前
高挑的荆关注了科研通微信公众号
7秒前
酷波er应助下一秒微笑采纳,获得10
7秒前
zjx完成签到,获得积分10
7秒前
Native007应助Nioy采纳,获得10
8秒前
李小木子发布了新的文献求助10
9秒前
果粒橙完成签到,获得积分20
9秒前
10秒前
panda完成签到,获得积分10
10秒前
端庄浩轩完成签到,获得积分10
11秒前
14秒前
14秒前
panda发布了新的文献求助10
15秒前
研友_yLpzpZ发布了新的文献求助10
15秒前
16秒前
17秒前
19秒前
11应助住在魔仙堡的鱼采纳,获得10
20秒前
20秒前
脑洞疼应助卫元灵采纳,获得10
21秒前
21秒前
高分求助中
【本贴是提醒信息,请勿应助】请在求助之前详细阅读求助说明!!!! 20000
One Man Talking: Selected Essays of Shao Xunmei, 1929–1939 1000
The Three Stars Each: The Astrolabes and Related Texts 900
Yuwu Song, Biographical Dictionary of the People's Republic of China 800
Multifunctional Agriculture, A New Paradigm for European Agriculture and Rural Development 600
Challenges, Strategies, and Resiliency in Disaster and Risk Management 500
Bernd Ziesemer - Maos deutscher Topagent: Wie China die Bundesrepublik eroberte 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 有机化学 工程类 生物化学 纳米技术 物理 内科学 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 电极 光电子学 量子力学
热门帖子
关注 科研通微信公众号,转发送积分 2481991
求助须知:如何正确求助?哪些是违规求助? 2144498
关于积分的说明 5470272
捐赠科研通 1866943
什么是DOI,文献DOI怎么找? 928005
版权声明 563071
科研通“疑难数据库(出版商)”最低求助积分说明 496455