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Nuclear Accumulation of YTHDF1 Regulates mRNA Splicing in the DNA Damage Response

GSE247891 Homo sapiens Expression profiling by high throughput sequencing; Other 8 samples Submitted 2025/03/12 Platform GPL24676
Summary
YTH domain-containing family protein 1 (YTHDF1), a reader of N6-methyladenosine, 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 ATR-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 SRSF2 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. Altogether, our study reveals a crucial role of YTHDF1 in m6A-mediated mRNA splicing in the DNA damage response, proposing it as a potential target for radiation therapy.
Published in
Nuclear accumulation of YTHDF1 regulates mRNA splicing in the DNA damage response
Hou J, Gao Y, Han B et al. · Science advances 2025 · PMID 40238889 · doi:10.1126/sciadv.ado7660
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Also filed as BioProject PRJNA1040876 and SRA study SRP472178. Searching any of these in the dataset finder brings you back here.

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