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YTHDC1 通过非依赖于 m6A 的方式激活 ATR 来延缓细胞衰老和肺纤维化。

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

机构信息

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

Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.

出版信息

EMBO J. 2024 Jan;43(1):61-86. doi: 10.1038/s44318-023-00003-2. Epub 2023 Dec 15.

DOI:10.1038/s44318-023-00003-2
PMID:38177310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10883269/
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.

摘要

DNA 损伤在肺部的积累会诱导细胞衰老，并促进特发性肺纤维化（IPF）等与年龄相关的疾病。因此，了解 DNA 损伤修复的机制调节对于抗衰老治疗和疾病控制非常重要。在这里，我们发现 RNA 结合蛋白 YTHDC1 在对抗应激诱导的肺衰老和纤维化方面具有非依赖 m6A 的作用。YTHDC1 主要在肺肺泡上皮细胞 2 型（AECII）中表达，并且在纤维化过程中 AECII 中的表达显著降低。外源性过表达 YTHDC1 可减轻肺衰老和纤维化，而 YTHDC1 缺失则会促进小鼠疾病的进展。在机制上，YTHDC1 促进 TopBP1 和 MRE11 之间的相互作用，从而激活 ATR 并促进 DNA 损伤修复。这些发现揭示了 YTHDC1 在延缓细胞衰老方面的非典型功能，并表明增强肺部的 YTHDC1 表达可能是治疗肺纤维化的有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/b22a21cbf109/44318_2023_3_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/da9a0b46fcc5/44318_2023_3_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/14581dc5f754/44318_2023_3_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/c3cc40ce878f/44318_2023_3_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/53d24b083bc5/44318_2023_3_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/769485cf1254/44318_2023_3_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/4d126c9d10fe/44318_2023_3_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/b22a21cbf109/44318_2023_3_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/70478c924c9a/44318_2023_3_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/868b7f3d8dad/44318_2023_3_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/42dc8bc889fe/44318_2023_3_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/5e99aee57128/44318_2023_3_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/da9a0b46fcc5/44318_2023_3_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/14581dc5f754/44318_2023_3_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/c3cc40ce878f/44318_2023_3_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/53d24b083bc5/44318_2023_3_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/769485cf1254/44318_2023_3_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/4d126c9d10fe/44318_2023_3_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/407b/10883269/b22a21cbf109/44318_2023_3_Fig11_ESM.jpg

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引用本文的文献

[1]
Hallmarks and mechanisms of cellular senescence in aging and disease.

Cell Death Discov. 2025-8-4

[2]
DNA damage response and cell fate decisions across the lifespan: from fetal development to age-related respiratory diseases.

Cell Biosci. 2025-8-2

[3]
Hallmarks of cellular senescence: biology, mechanisms, regulations.

Exp Mol Med. 2025-7-10

[4]
ALKBH5 regulates intrauterine adhesion progression through m6A dependent FABP4 mRNA stabilization and serum lipid metabolism.

Commun Biol. 2025-7-1

[5]
The critical role of mitophagy in cell senescence-mediated pulmonary fibrosis and potential therapeutic strategies.

Mol Biol Rep. 2025-6-7

[6]
SuoquanYishen formula improves renal cellular senescence by inhibiting YTHDF1-Rubicon axis to promote autophagy in diabetic kidney disease.

Front Pharmacol. 2025-4-30

[7]
Mitochondrial dysfunction and alveolar type II epithelial cell senescence: The destroyer and rescuer of idiopathic pulmonary fibrosis.

Front Cell Dev Biol. 2025-3-31

[8]
m6A Ribonucleic Acid Methylation in Fibrotic Diseases of Visceral Organs.

Small Sci. 2024-11-21

[9]
Identification and validation of CDC20 and ITCH as ubiquitination related biomarker in idiopathic pulmonary fibrosis.

Hereditas. 2025-4-1

[10]
The role of N(6)-methyladenosine (m6a) modification in cancer: recent advances and future directions.

EXCLI J. 2025-1-15

本文引用的文献

[1]
Genome-Wide Native R-Loop Profiling by R-Loop Cleavage Under Targets and Tagmentation (R-Loop CUT&Tag).

Methods Mol Biol. 2022

[2]
Roles and mechanisms of the mA reader YTHDC1 in biological processes and diseases.

Cell Death Discov. 2022-5-2

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The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of mA recognition.

Mol Cell. 2022-5-5

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Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis.

Cells. 2022-3-3

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A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.

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Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation.

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A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication.

Blood. 2021-12-30

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