YTHDC1 Delays Cellular Senescence and Pulmonary Fibrosis by Activating ATR in an M6A-independent Manner

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Jan 4

PMID 38177310

Authors

Canfeng Zhang

Liping Chen

Chen Xie

Fengwei Wang

Juan Wang

Haoxian Zhou

Qianyi Liu

Zhuo Zeng

Na Li

Junjiu Huang

Yong Zhao

Haiying Liu

Affiliations

Soon will be listed here.

Abstract

Accumulation 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.

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