Author:
Mayerle Megan,Yitiz Samira,Soulette Cameron,Rogel Lucero E.,Ramirez Andrea,Ragle J. Matthew,Katzman Sol,Guthrie Christine,Zahler Alan M.
Abstract
Pre-mRNA splicing must occur with extremely high fidelity. Spliceosomes assemble onto pre-mRNA guided by specific sequences (5′ splice site, 3′ splice site, and branchpoint). When splice sites are mutated, as in many hereditary diseases, the spliceosome can aberrantly select nearby pseudo- or “cryptic” splice sites, often resulting in nonfunctional protein. How the spliceosome distinguishes authentic splice sites from cryptic splice sites is poorly understood. We performed aCaenorhabditis elegansgenetic screen to find cellular factors that affect the frequency with which the spliceosome uses cryptic splice sites and identified two alleles in core spliceosome component Prp8 that alter cryptic splicing frequency. Subsequent complementary genetic and structural analyses in yeast implicate these alleles in the stability of the spliceosome’s catalytic core. However, despite a clear effect on cryptic splicing, high-throughput mRNA sequencing of theseprp-8mutantC. elegansreveals that overall alternative splicing patterns are relatively unchanged. Our data suggest the spliceosome evolved intrinsic mechanisms to reduce the occurrence of cryptic splicing and that these mechanisms are distinct from those that impact alternative splicing.
Funder
National Science Foundation
HHS | NIH | National Institute of General Medical Sciences
Publisher
Proceedings of the National Academy of Sciences
Cited by
12 articles.
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