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

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

EMBO J

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

Published: January 2024

AI Article Synopsis

  • Accumulation of DNA damage in the lungs leads to cellular senescence, contributing to age-related diseases like idiopathic pulmonary fibrosis (IPF), making DNA repair mechanisms crucial for anti-aging and disease management.
  • Researchers discovered a crucial role of the RNA-binding protein YTHDC1 in preventing stress-induced pulmonary senescence and fibrosis, particularly in pulmonary alveolar epithelial type 2 (AECII) cells, where its expression decreases during fibrosis.
  • Overexpressing YTHDC1 can reduce pulmonary senescence and fibrosis without its m6A-binding function, while its deletion worsens disease in mice; YTHDC1 aids DNA damage repair by enhancing the interaction between TopBP1 and MRE11 and activating ATR, highlighting its

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883269PMC
http://dx.doi.org/10.1038/s44318-023-00003-2DOI Listing

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