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Although the transcriptomes of cells undergoing senescence are strongly regulated, the landscape and impact of m6A modifications during senescence are poorly understood. Here, we report a robust m6A modification of PTCHD4 mRNA, encoding Patched Domain-Containing Protein 4, in senescent cells. The METTL3\/METTL14 complex was found to incorporate the m6A modification on PTCHD4 mRNA; addition of m6A rendered PTCHD4 mRNA more stable and increased PTCHD4 production. MeRIP RT-qPCR and eCLIP analyses were used to map this m6A modification to the last exon of PTCHD4 mRNA. Further investigation identified IGF2BP1, but not other m6A readers, as responsible for the stabilization and increased abundance of m6A-modified PTCHD4 mRNA. Silencing PTCHD4, a transmembrane protein, enhanced growth arrest and DNA damage in pre-senescent cells and sensitized them to senolysis and apoptosis. Our results indicate that m6A modification of PTCHD4 mRNA increases the production of PTCHD4, a protein associated with senescent cell survival, supporting the notion that regulating m6A modification on specific mRNAs could be exploited to eliminate senescent cells for therapeutic benefit.<\/jats:p>","DOI":"10.1093\/nar\/gkae322","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T11:24:40Z","timestamp":1712921080000},"page":"7261-7278","source":"Crossref","is-referenced-by-count":23,"title":["Increased PTCHD4 expression via m6A modification of\n                    <i>PTCHD4<\/i>\n                    mRNA promotes senescent cell survival"],"prefix":"10.1093","volume":"52","author":[{"given":"Martina","family":"Rossi","sequence":"first","affiliation":[{"name":"Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH) , Baltimore , MD , 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