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


ABSTRACT: Accumulated DNA damages will induce cellular senescence and promote age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the fundamental mechanism of DNA damage repair is particularly important for anti-aging and aging disease therapy. Here, we identified an m6A-independent role of YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 primarily expresses in pulmonary alveolar epithelial type 2 (AECII) cells and its expression is significantly decreased in AECII during pulmonary fibrosis. In addition, overexpression of YTHDC1, even with the m6A binding domain mutated, alleviates pulmonary senescence and fibrosis, whereas YTHDC1 deficiency deteriorates the disease progress. Mechanistic studies revealed that YTHDC1 promotes the interaction between TopBP1 and MRE11, thus activating the ATR and facilitating the DNA damage repair. These findings demonstrate an uncanonical 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.

ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)

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PROVIDER: S-BSST1109 | biostudies-other |

REPOSITORIES: biostudies-other

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