RESUMEN

N6-methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S-adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A's last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3's role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3's complex role as an RNA-binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes.

Asunto(s)

Adenosina , Metionina Adenosiltransferasa , Metiltransferasas , Neoplasias , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Metionina Adenosiltransferasa/metabolismo , Metionina Adenosiltransferasa/genética , Neoplasias/genética , Neoplasias/metabolismo , Metilación , Línea Celular Tumoral , S-Adenosilmetionina/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Empalme del ARN/genética , Animales , Ratones , ARN/metabolismo , ARN/genética , Procesamiento Postranscripcional del ARN , Metilación de ARN