YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner

Author:

Zhang CanfengORCID,Chen Liping,Xie Chen,Wang Fengwei,Wang Juan,Zhou HaoxianORCID,Liu QianyiORCID,Zeng Zhuo,Li Na,Huang Junjiu,Zhao YongORCID,Liu HaiyingORCID

Abstract

AbstractAccumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

Funder

MOST | National Natural Science Foundation of China

Guangdong Basic and Applied Basic Research Foundation

Shenzhen Science and Technology Program

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The m6A‐independent role of epitranscriptomic factors in cancer;International Journal of Cancer;2024-06-27

2. The role of epithelial cells in fibrosis: Mechanisms and treatment;Pharmacological Research;2024-04

3. Promoting DNA repair to prevent fibrosis;Science Signaling;2024-01-23

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