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m6A modula la traducción RAN desde el ARN de expansión de repetición CAG
Yuxiang Sun1,2, Zhouxian Li1, Hui Dai1
1Department of Chemistry, University of California Riverside, Riverside, CA 92521-0403.
Aggregate (Hoboken, N.J.)
|August 29, 2025
Resumen
La metilación (m6A) promueve la traducción no asociada a la repetición (RAN) de las repeticiones CAG expandidas en la ataxia espinocerebelosa tipo 3 (SCA3). METTL3 facilita este proceso, mientras que FTO elimina la marca de metilación, lo que afecta a los productos de traducción RAN.
Área de la Ciencia:
- La neurociencia
- Biología molecular
- La genética
Sus antecedentes:
- Las expansiones de repetición de nucleótidos están implicadas en enfermedades neurodegenerativas.
- La traducción no-AUG (RAN) asociada a la repetición del ARN expandido es un mecanismo conocido pero mal entendido.
Objetivo del estudio:
- Elucidar los mecanismos que regulan la traducción de RAN desde el ARN de repetición CAG expandido.
- Para investigar el papel de la metilación del ARN, específicamente m6A, en este proceso.
Principales métodos:
- Investigó el papel de METTL3 (escritor) y FTO (borrador) en la traducción RAN.
- Utilizó agotamiento genético, inhibición farmacológica y expresión ectópica de METTL3.
- Los productos de traducción RAN analizados del ARN de repetición CAG expandido del gen ATXN3 humano.
Principales resultados:
- Una modificación, instalada por METTL3 y eliminada por FTO, promueve la traducción RAN en los tres marcos de lectura.
- El agotamiento/inhibición de METTL3 redujo los productos RAN; la restauración se produjo con el METTL3 de tipo salvaje, pero no con el mutante inactivo.
- La ablación de FTO aumentó los productos RAN.
- Los agregados de poli (serina) RAN se forman en forma de gel.
Conclusiones:
- m6 juega un papel crítico en la modulación de la traducción RAN del ARN de repetición CAG expandido en SCA3.
- Se han identificado nuevas propiedades biofísicas del producto de traducción RAN de poli (serina).
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