Principles and Correction of 5'-splice Site Selection

Overview

Journal RNA Biol

Specialty Molecular Biology

Date 2022 Jul 22

PMID 35866748

Authors

Florian Malard

Cameron D Mackereth

Sebastien Campagne

Affiliations

Soon will be listed here.

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 , and further regulation of the retained exons leads to alternatively spliced mRNA. The 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 (5'ss) 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 5'ss 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 5'ss selection by U1 snRNP, and discuss recent therapeutic advances that manipulate U1 snRNP 5'ss selectivity with antisense oligonucleotides and small-molecule splicing switches.

Citing Articles

Generation of Transcript Length Variants and Reprogramming of mRNA Splicing During Atherosclerosis Progression in ApoE-Deficient Mice.

Hueso M, Mallen A, Navarro E Biomedicines. 2025; 12(12.

PMID: 39767610 PMC: 11672872. DOI: 10.3390/biomedicines12122703.

A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP.

White D, Dunyak B, Vaillancourt F, Hoskins A Nat Commun. 2024; 15(1):8776.

PMID: 39389991 PMC: 11467380. DOI: 10.1038/s41467-024-53124-5.

Small molecules modulating RNA splicing: a review of targets and future perspectives.

Bouton L, Ecoutin A, Malard F, Campagne S RSC Med Chem. 2024; 15(4):1109-1126.

PMID: 38665842 PMC: 11042171. DOI: 10.1039/d3md00685a.

A Sequential Binding Mechanism for 5' Splice Site Recognition and Modulation for the Human U1 snRNP.

White D, Dunyak B, Vaillancourt F, Hoskins A bioRxiv. 2024; .

PMID: 38659798 PMC: 11042371. DOI: 10.1101/2024.04.18.590139.

The diversity of splicing modifiers acting on A-1 bulged 5'-splice sites reveals rules for rational drug design.

Malard F, Wolter A, Marquevielle J, Morvan E, Ecoutin A, Rudisser S Nucleic Acids Res. 2024; 52(8):4124-4136.

PMID: 38554107 PMC: 11077090. DOI: 10.1093/nar/gkae201.

References

Porensky P, Mitrpant C, McGovern V, Bevan A, Foust K, Kaspar B . A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2011; 21(7):1625-38. PMC: 3298284. DOI: 10.1093/hmg/ddr600. View

Zhang S, Aibara S, Vos S, Agafonov D, Luhrmann R, Cramer P . Structure of a transcribing RNA polymerase II-U1 snRNP complex. Science. 2021; 371(6526):305-309. DOI: 10.1126/science.abf1870. View

Meijboom K, Wood M, McClorey G . Splice-Switching Therapy for Spinal Muscular Atrophy. Genes (Basel). 2017; 8(6). PMC: 5485525. DOI: 10.3390/genes8060161. View

Brosius J, Raabe C . What is an RNA? A top layer for RNA classification. RNA Biol. 2016; 13(2):140-4. PMC: 4829331. DOI: 10.1080/15476286.2015.1128064. View

Cho S, Hoang A, Sinha R, Zhong X, Fu X, Krainer A . Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70K snRNP protein determines early spliceosome assembly. Proc Natl Acad Sci U S A. 2011; 108(20):8233-8. PMC: 3100968. DOI: 10.1073/pnas.1017700108. View

Bessa C, Matos P, Jordan P, Goncalves V . Alternative Splicing: Expanding the Landscape of Cancer Biomarkers and Therapeutics. Int J Mol Sci. 2020; 21(23). PMC: 7729450. DOI: 10.3390/ijms21239032. View

Sathasivam K, Neueder A, Gipson T, Landles C, Benjamin A, Bondulich M . Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A. 2013; 110(6):2366-70. PMC: 3568346. DOI: 10.1073/pnas.1221891110. View

Stormo G, Schneider T, Gold L, Ehrenfeucht A . Use of the 'Perceptron' algorithm to distinguish translational initiation sites in E. coli. Nucleic Acids Res. 1982; 10(9):2997-3011. PMC: 320670. DOI: 10.1093/nar/10.9.2997. View

Chen W, Lv G, Lv C, Zeng C, Hu S . Systematic analysis of alternative first exons in plant genomes. BMC Plant Biol. 2007; 7:55. PMC: 2174465. DOI: 10.1186/1471-2229-7-55. View

10.

Van Nostrand E, Freese P, Pratt G, Wang X, Wei X, Xiao R . A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020; 583(7818):711-719. PMC: 7410833. DOI: 10.1038/s41586-020-2077-3. View

11.

Wang I, Hennig J, Jagtap P, Sonntag M, Valcarcel J, Sattler M . Structure, dynamics and RNA binding of the multi-domain splicing factor TIA-1. Nucleic Acids Res. 2014; 42(9):5949-66. PMC: 4027183. DOI: 10.1093/nar/gku193. View

12.

Huot M, Vogel G, Zabarauskas A, Ngo C, Coulombe-Huntington J, Majewski J . The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis. Mol Cell. 2012; 46(2):187-99. DOI: 10.1016/j.molcel.2012.02.007. View

13.

Wang R, Wang Z, Wang J, Li S . SpliceFinder: ab initio prediction of splice sites using convolutional neural network. BMC Bioinformatics. 2019; 20(Suppl 23):652. PMC: 6933889. DOI: 10.1186/s12859-019-3306-3. View

14.

Crick F . Split genes and RNA splicing. Science. 1979; 204(4390):264-71. DOI: 10.1126/science.373120. View

15.

Wilkinson M, Charenton C, Nagai K . RNA Splicing by the Spliceosome. Annu Rev Biochem. 2019; 89:359-388. DOI: 10.1146/annurev-biochem-091719-064225. View

16.

Pomeranz Krummel D, Oubridge C, Leung A, Li J, Nagai K . Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution. Nature. 2009; 458(7237):475-80. PMC: 2673513. DOI: 10.1038/nature07851. View

17.

Sharma S, Maris C, Allain F, Black D . U1 snRNA directly interacts with polypyrimidine tract-binding protein during splicing repression. Mol Cell. 2011; 41(5):579-88. PMC: 3931528. DOI: 10.1016/j.molcel.2011.02.012. View

18.

Bushby K, Finkel R, Birnkrant D, Case L, Clemens P, Cripe L . Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2009; 9(1):77-93. DOI: 10.1016/S1474-4422(09)70271-6. View

19.

Herai R, Negraes P, Muotri A . Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. Hum Mol Genet. 2017; 26(13):2472-2479. PMC: 6075211. DOI: 10.1093/hmg/ddx142. View

20.

Xiao S, Manley J . Phosphorylation of the ASF/SF2 RS domain affects both protein-protein and protein-RNA interactions and is necessary for splicing. Genes Dev. 1997; 11(3):334-44. DOI: 10.1101/gad.11.3.334. View