Journal Article

Recognition of atypical 5′ splice sites by shifted base-pairing to U1 snRNA

Krainer, Adrian R, Roca, Xavier

2009

Overview

One of the key early steps in splicing is recognition of the 5′ splice site by base-pairing to the U1 small nuclear RNA. Data now indicate that U1 can shift to recognize what had been designated as atypical 5′ splice sites, broadening the scope of what can be recognized as a functional splice site by the canonical machinery and thus impacting both splicing predictions and mechanism, as well as providing a potential mechanism underlying a puzzling mutation associated with pontocerebellar hypoplasia. Accurate pre-mRNA splicing is crucial for gene expression. The 5′ splice site (5′ ss)—the highly diverse element at the 5′ end of introns—is initially recognized via base-pairing to the 5′ end of the U1 small nuclear RNA (snRNA). However, many natural 5′ ss have a poor match to the consensus sequence, and are predicted to be weak. Using genetic suppression experiments in human cells, we demonstrate that some atypical 5′ ss are actually efficiently recognized by U1, in an alternative base-pairing register that is shifted by one nucleotide. These atypical 5′ ss are phylogenetically widespread, and many of them are conserved. Moreover, shifted base-pairing provides an explanation for the effect of a 5′ ss mutation associated with pontocerebellar hypoplasia. The unexpected flexibility in 5′ ss–U1 base-pairing challenges an established paradigm and has broad implications for splice-site prediction algorithms and gene-annotation efforts in genome projects.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Algorithms / Animals / Base Pairing / Base Sequence / Biochemistry / Biological Microscopy / Biomedical and Life Sciences / Cellular biology / Experiments / Gene expression / HeLa Cells / Humans / Life Sciences / Membrane Biology / Molecular biology / Mutation / Nucleic Acid Conformation / Physiological aspects / Protein Structure / Ribonucleic acid / RNA / RNA Splice Sites / RNA Splicing / RNA, Small Nuclear - chemistry / RNA, Small Nuclear - metabolism / Small nuclear ribonucleoproteins / Structure