Prp40 and early events in splice site definition.
The alternative splicing (AS) of precursor messenger RNA (pre-mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre-mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active-site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre-mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17-32. doi: 10.1002/wrna.1312 For further resources related to this article, please visit the WIREs website.
Department of Molecular Biology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), PTS Granada 18016, Spain.
Soraya
S
Becerra
Bioinformatics Unit, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), PTS Granada 18016, Spain.
Eduardo
http://orcid.org/0000-0002-0621-9914
E
Andrés-León
Department of Molecular Biology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), PTS Granada 18016, Spain.
Silvia
S
Prieto-Sánchez
Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), PTS Granada 18016, Spain.
Cristina
C
Hernández-Munain
Department of Molecular Biology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), PTS Granada 18016, Spain.
Carlos
http://orcid.org/0000-0002-7991-0458
C
Suñé
D017398:Alternative Splicing; D002352:Carrier Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons; D006801:Humans; D007438:Introns; D017434:Protein Structure, Tertiary; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D017381:Spliceosomes
D002352:Carrier Proteins; C491404:PRPF40A protein, human; C000596821:PRPF40B protein, human; C120813:Prp40 protein, S cerevisiae; D017412:Ribonucleoprotein, U1 Small Nuclear; D029701:Saccharomyces cerevisiae Proteins