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La proteína arginina metiltransferasa 5 mantiene el complejo Tip60-EP400 a través de SRSF1 en el carcinoma de células

Joseph L Sevigny^1,2, Evelyn V Proctor¹, Heather Adams¹

¹Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA.

Life science alliance

|August 22, 2025

Resumen

La proteína arginina metiltransferasa 5 (PRMT5) regula el empalme del ARN mediante la modificación de SRSF1, crucial para la actividad del complejo Tip60-EP400 en los cánceres impulsados por MYCL. La inhibición de PRMT5 causa defectos de empalme, ofreciendo estrategias terapéuticas potenciales.

Área de la Ciencia:

Biología molecular
Genómica del cáncer
La epigenética

Sus antecedentes:

La proteína arginina metiltransferasa 5 (PRMT5) es un regulador clave de la expresión génica y el empalme del ARN.
La inhibición de PRMT5 muestra potencial terapéutico en cánceres eliminados por MTAP.
Los tumores impulsados por MYC o aquellos con TP53 de tipo salvaje también pueden responder a la inhibición de PRMT5, pero los mecanismos no están claros.

Objetivo del estudio:

Investigar el papel de PRMT5 en la regulación del complejo Tip60-EP400 en el carcinoma de células Merkel impulsado por MYCL.
Caracterizar la expresión génica mediada por PRMT5 y el empalme alternativo utilizando RNA-seq e Iso-Seq.
Aclarar los mecanismos moleculares subyacentes a la función de PRMT5 en la regulación del empalme.

Principales métodos:

Secuenciación de ARN (RNA-seq) para analizar la expresión génica mediada por PRMT5.
Iso-Seq para el análisis en profundidad del empalme alternativo mediado por PRMT5.
Se investigó la interacción entre PRMT5, SRSF1 y el complejo Tip60-EP400.

Principales resultados:

La modificación PRMT5 de SRSF1 mejora su reclutamiento al ARN modificado por m6A, asegurando el empalme adecuado de KAT5 (Tip60) y la actividad de Tip60-EP400.
La inhibición de PRMT5 conduce a defectos de empalme generalizados, incluido el salto de exones y la retención de intrones.
Se observó una interrupción del reclutamiento de SRSF1 al ARN modificado por m6A tras la inhibición de PRMT5.

Conclusiones:

PRMT5 juega un papel crítico en la regulación del empalme, particularmente en los cánceres impulsados por MYCL.
La inhibición de PRMT5 interrumpe el empalme normal al afectar el reclutamiento de SRSF1, lo que lleva a una desregulación de la vía oncogénica.
Dirigirse a la desregulación de empalme mediada por PRMT5 podría ser una estrategia terapéutica para los cánceres impulsados por MYC.

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