RESUMEN
Alternative splicing of terminal exons increases transcript and protein diversity. How physiological and pathological stimuli regulate the choice between alternative terminal exons is, however, largely unknown. Here, we show that Brahma (BRM), the ATPase subunit of the hSWI/SNF chromatin-remodeling complex interacts with BRCA1/BARD1, which ubiquitinates the 50 kDa subunit of the 3' end processing factor CstF. This results in the inhibition of transcript cleavage at the proximal poly(A) site and a shift towards inclusion of the distal terminal exon. Upon oxidative stress, BRM is depleted, cleavage inhibition is released, and inclusion of the proximal last exon is favoored. Our findings elucidate a novel regulatory mechanism, distinct from the modulation of transcription elongation by BRM that controls alternative splicing of internal exons.
Asunto(s)
Empalme Alternativo , Proteína BRCA1/metabolismo , Factor de Estimulación del Desdoblamiento/metabolismo , Exones , Estrés Oxidativo , Transducción de Señal , Factores de Transcripción/metabolismo , Adenosina Trifosfatasas/metabolismo , Línea Celular Tumoral , Regulación de la Expresión Génica , Humanos , Complejos Multiproteicos , Estrés Oxidativo/genética , Poli A , Unión Proteica , Factores de Transcripción/genética , UbiquitinaciónRESUMEN
Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs. This review will highlight recent advances in the understanding of the role of RBPs in the regulation of the maturation and the function of miRNAs. The interplay between miRNAs and RBPs is discussed specifically in the context of neuronal development and function.