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

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.

DNA损伤累积可诱导细胞衰老，并促进特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）等衰老相关疾病的发生发展。因此，解析DNA损伤修复的核心机制，对于抗衰老及衰老相关疾病的治疗具有重要意义。本研究鉴定出YTHDC1具备不依赖m⁶A（m6A）的功能，可拮抗应激诱导的肺衰老与肺纤维化。YTHDC1主要表达于肺泡II型上皮细胞（pulmonary alveolar epithelial type 2, AECII）中，在肺纤维化进程中，该类细胞内YTHDC1的表达水平显著下调。此外，即便YTHDC1的m⁶A结合结构域发生突变，过表达YTHDC1仍可缓解肺衰老与肺纤维化；而YTHDC1缺失则会加重疾病进展。机制研究显示，YTHDC1可促进TopBP1与MRE11的相互作用，进而激活ATR通路并加速DNA损伤修复。上述研究结果揭示了YTHDC1在延缓细胞衰老方面的非经典功能，并提示增强肺部YTHDC1的表达可作为肺纤维化的有效治疗策略。