Nuclear accumulation of YTHDF1 regulates mRNA splicing in the DNA damage response

YTH domain-containing family protein 1 (YTHDF1), a reader of N6-methyladenosine (m⁶A), has been implicated in regulating RNA metabolism in the cytosol. Here, we report a role of YTHDF1 within the nucleus in response to genotoxic stress. Upon radiation, YTHDF1 is phosphorylated at serine-182 in an ataxia telangiectasia and Rad3-related-dependent manner. This phosphorylation inhibits exportin 1-mediated nuclear export of YTHDF1, resulting in its accumulation within the nucleus. Nuclear YTHDF1 enhances the binding capacity of serine- and arginine-rich splicing factor 2 to a group of m⁶A-modified exons, leading to increased exon inclusion. Specifically, YTHDF1 promotes splicing and expression of DNA repair genes, such as BRCA1 and TP53BP1, thereby mitigating excessive DNA damage. Depletion of YTHDF1 sensitizes cancer cells to radiation treatment. Together, our study reveals a crucial role of YTHDF1 in m⁶A-mediated messenger RNA splicing in the DNA damage response, proposing it as a potential target for radiation therapy.