RESUMEN
Splicing of the precursor messenger RNA, involving intron removal and exon ligation, is mediated by the spliceosome. Together with biochemical and genetic investigations of the past four decades, structural studies of the intact spliceosome at atomic resolution since 2015 have led to mechanistic delineation of RNA splicing with remarkable insights. The spliceosome is proven to be a protein-orchestrated metalloribozyme. Conserved elements of small nuclear RNA (snRNA) constitute the splicing active site with two catalytic metal ions and recognize three conserved intron elements through duplex formation, which are delivered into the splicing active site for branching and exon ligation. The protein components of the spliceosome stabilize the conformation of the snRNA, drive spliceosome remodeling, orchestrate the movement of the RNA elements, and facilitate the splicing reaction. The overall organization of the spliceosome and the configuration of the splicing active site are strictly conserved between human and yeast.
Asunto(s)
Factores de Empalme de ARN/genética , Empalme del ARN , Proteínas de Unión al ARN/genética , Ribonucleoproteína Nuclear Pequeña U4-U6/genética , Ribonucleoproteína Nuclear Pequeña U5/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Empalmosomas/metabolismo , Dominio Catalítico , Secuencia Conservada , Exones , Humanos , Intrones , Modelos Moleculares , Conformación de Ácido Nucleico , Estructura Secundaria de Proteína , ARN Helicasas/química , ARN Helicasas/genética , ARN Helicasas/metabolismo , Precursores del ARN/química , Precursores del ARN/genética , Precursores del ARN/metabolismo , Factores de Empalme de ARN/química , Factores de Empalme de ARN/metabolismo , ARN Nuclear Pequeño/química , ARN Nuclear Pequeño/genética , ARN Nuclear Pequeño/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteína Nuclear Pequeña U4-U6/química , Ribonucleoproteína Nuclear Pequeña U4-U6/metabolismo , Ribonucleoproteína Nuclear Pequeña U5/química , Ribonucleoproteína Nuclear Pequeña U5/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Empalmosomas/genética , Empalmosomas/ultraestructuraRESUMEN
Proper gene expression requires the collaborative effort of multiple macromolecular machines to produce functional messenger RNA. As RNA polymerase II (RNA Pol II) transcribes DNA, the nascent pre-messenger RNA is heavily modified by other complexes such as 5' capping enzymes, the spliceosome, the cleavage, and polyadenylation machinery as well as RNA-modifying/editing enzymes. Recent evidence has demonstrated that pre-mRNA splicing and 3' end cleavage can occur on similar timescales as transcription and significantly cross-regulate. In this review, we discuss recent advances in co-transcriptional processing and how it contributes to gene regulation. We highlight how emerging areas-including coordinated splicing events, physical interactions between the RNA synthesis and modifying machinery, rapid and delayed splicing, and nuclear organization-impact mRNA isoforms. Coordination among RNA-processing choices yields radically different mRNA and protein products, foreshadowing the likely regulatory importance of co-transcriptional RNA folding and co-transcriptional modifications that have yet to be characterized in detail.