RESUMEN
N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m6A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m6A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.
Asunto(s)
Adenosina/análogos & derivados , Núcleo Celular/metabolismo , Metilación de ADN , Leucemia Mieloide Aguda/prevención & control , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Empalme de ARN/metabolismo , ARN Mensajero/metabolismo , Adenosina/química , Adenosina/metabolismo , Animales , Apoptosis , Diferenciación Celular , Núcleo Celular/genética , Proliferación Celular , Femenino , Hematopoyesis , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Extracción Líquido-Líquido , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas del Tejido Nervioso/genética , Transición de Fase , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Empalme de ARN/genética , Estabilidad del ARN , ARN Mensajero/química , ARN Mensajero/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n ATRX mutations are found in nearly all tumours that maintain their telomeres via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX Here, we show loss of ATRX is also associated with increased R-loop formation. Our data suggest that the presence of ATRX at telomeres may have a central role in suppressing deleterious DNA secondary structures that form at transcribed telomeric repeats, and this may account for the increased DNA damage, stalling of replication and homology-directed repair previously observed upon loss of ATRX function.
