Nuclear accumulation of YTHDF1 regulates mRNA splicing in the DNA damage response.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40238889.
- Also identified by DOI 10.1126/sciadv.ado7660 and PMC identifier 12002136.
- Licence recorded as CC BY-NC.
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Abstract
YTH domain-containing family protein 1 (YTHDF1), a reader of N6-methyladenosine (m<sup>6</sup>A), 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 m<sup>6</sup>A-modified exons, leading to increased exon inclusion. Specifically, YTHDF1 promotes splicing and expression of DNA repair genes, such as <i>BRCA1</i> and <i>TP53BP1</i>, thereby mitigating excessive DNA damage. Depletion of YTHDF1 sensitizes cancer cells to radiation treatment. Together, our study reveals a crucial role of YTHDF1 in m<sup>6</sup>A-mediated messenger RNA splicing in the DNA damage response, proposing it as a potential target for radiation therapy.
Medical subject headings
- DNA Damage
- RNA-Binding Proteins
- RNA Splicing
- Cell Nucleus
- RNA, Messenger
- RNA Splicing Factors