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YTHDC1 m6A-dependent and m6A-independent functions converge to preserve the DNA damage response.
Elvira-Blázquez, Daniel; Fernández-Justel, José Miguel; Arcas, Aida; Statello, Luisa; Goñi, Enrique; González, Jovanna; Ricci, Benedetta; Zaccara, Sara; Raimondi, Ivan; Huarte, Maite.
Afiliación
  • Elvira-Blázquez D; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • Fernández-Justel JM; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
  • Arcas A; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • Statello L; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
  • Goñi E; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • González J; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
  • Ricci B; Clarivate, Barcelona, Spain.
  • Zaccara S; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • Raimondi I; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
  • Huarte M; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
EMBO J ; 43(16): 3494-3522, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38951610
ABSTRACT
Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response. Among the top hits, we find the m6A reader YTHDC1 as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in the DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency also causes the retention of introns and therefore aberrant protein production of key DNA damage factors. While YTHDC1-mediated intron retention requires m6A, TP53 transcriptional pause-release is promoted by YTHDC1 independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Proteína p53 Supresora de Tumor Límite: Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Proteína p53 Supresora de Tumor Límite: Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido