Principles and correction of 5’-splice site selection

Abstract

In Eukarya, immature mRNA transcripts (pre-mRNA) often contain coding sequences, or exons, interleaved by non-coding sequences, or introns. Introns are removed upon splicing, and further regulation of the retained exons leads to alternatively spliced mRNA. The splicing reaction requires the stepwise assembly of the spliceosome, a macromolecular machine composed of small nuclear ribonucleoproteins (snRNPs). This review focuses on the early stage of spliceosome assembly, when U1 snRNP defines each intron 5’-splice site (5ʹss) in the pre-mRNA. We first introduce the splicing reaction and the impact of alternative splicing on gene expression regulation. Thereafter, we extensively discuss splicing descriptors that influence the 5ʹss selection by U1 snRNP, such as sequence determinants, and interactions mediated by U1-specific proteins or U1 small nuclear RNA (U1 snRNA). We also include examples of diseases that affect the 5ʹss selection by U1 snRNP, and discuss recent therapeutic advances that manipulate U1 snRNP 5ʹss selectivity with antisense oligonucleotides and small-molecule splicing switches.

Keywords

• rna splicing
• 5’-splice site
• u1 snrnp
• antisense oligonucleotides
• splicing modifiers