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

Canfeng Zhang1,2, Liping Chen3, Chen Xie1

  • 1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

The EMBO Journal
|January 4, 2024
PubMed

Insights

The RNA-binding protein YTHDC1 counteracts lung aging and fibrosis by enhancing DNA damage repair in alveolar epithelial cells. Boosting YTHDC1 levels may treat pulmonary fibrosis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Aging Research

Background:

  • DNA damage accumulation in the lungs drives cellular senescence and age-related diseases like idiopathic pulmonary fibrosis (IPF).
  • Understanding DNA damage repair mechanisms is crucial for developing anti-aging therapies and managing lung diseases.

Purpose of the Study:

  • To investigate the role of the RNA-binding protein YTHDC1 in pulmonary senescence and fibrosis.
  • To elucidate the mechanism by which YTHDC1 regulates DNA damage repair.

Main Methods:

  • Investigated YTHDC1 expression in pulmonary alveolar epithelial type 2 (AECII) cells during fibrosis.
  • Utilized YTHDC1 overexpression and deletion models in mice to assess its impact on pulmonary senescence and fibrosis.
  • Examined the interaction between YTHDC1, TopBP1, and MRE11 to understand the molecular mechanism.

Main Results:

  • YTHDC1 expression decreases in AECII cells during fibrosis.
  • YTHDC1 overexpression alleviates pulmonary senescence and fibrosis independently of m6A binding.
  • YTHDC1 deletion exacerbates disease progression in mice.
  • YTHDC1 facilitates DNA damage repair by promoting TopBP1-MRE11 interaction and activating ATR.

Conclusions:

  • YTHDC1 plays a critical role in counteracting stress-induced pulmonary senescence and fibrosis through an m6A-independent mechanism.
  • YTHDC1 enhances DNA damage repair by modulating the TopBP1-MRE11-ATR pathway.
  • Increasing YTHDC1 expression in the lung presents a potential therapeutic strategy for pulmonary fibrosis.
Keywords:
ATRIPFSenescenceYTHDC1

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