Function of Alternative Splicing

Overview

Journal Gene

Specialty Molecular Biology

Date 2012 Aug 23

PMID 22909801

Citations 380

Authors

Olga Kelemen

Paolo Convertini

Zhaiyi Zhang

Yuan Wen

Manli Shen

Marina Falaleeva

Stefan Stamm

Affiliations

Soon will be listed here.

Abstract

Almost all polymerase II transcripts undergo alternative pre-mRNA splicing. Here, we review the functions of alternative splicing events that have been experimentally determined. The overall function of alternative splicing is to increase the diversity of mRNAs expressed from the genome. Alternative splicing changes proteins encoded by mRNAs, which has profound functional effects. Experimental analysis of these protein isoforms showed that alternative splicing regulates binding between proteins, between proteins and nucleic acids as well as between proteins and membranes. Alternative splicing regulates the localization of proteins, their enzymatic properties and their interaction with ligands. In most cases, changes caused by individual splicing isoforms are small. However, cells typically coordinate numerous changes in 'splicing programs', which can have strong effects on cell proliferation, cell survival and properties of the nervous system. Due to its widespread usage and molecular versatility, alternative splicing emerges as a central element in gene regulation that interferes with almost every biological function analyzed.

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References

Paradis C, Cloutier P, Shkreta L, Toutant J, Klarskov K, Chabot B . hnRNP I/PTB can antagonize the splicing repressor activity of SRp30c. RNA. 2007; 13(8):1287-300. PMC: 1924885. DOI: 10.1261/rna.403607. View

Mizuno M, Donev R, Harris C, Morgan B . CD55 in rat male reproductive tissue: differential expression in testis and expression of a unique truncated isoform on spermatozoa. Mol Immunol. 2006; 44(7):1613-22. DOI: 10.1016/j.molimm.2006.08.018. View

Mango R, Biocca S, del Vecchio F, Clementi F, Sangiuolo F, Amati F . In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ Res. 2005; 97(2):152-8. DOI: 10.1161/01.RES.0000174563.62625.8e. View

Lopez V, Kelleher S . Zinc transporter-2 (ZnT2) variants are localized to distinct subcellular compartments and functionally transport zinc. Biochem J. 2009; 422(1):43-52. PMC: 3381892. DOI: 10.1042/BJ20081189. View

Torrado M, Iglesias R, Centeno A, Lopez E, Mikhailov A . Exon-skipping brain natriuretic peptide variant is overexpressed in failing myocardium and attenuates brain natriuretic peptide production in vitro. Exp Biol Med (Maywood). 2010; 235(8):941-51. DOI: 10.1258/ebm.2010.010078. View

Israel D, Regan J . EP(3) prostanoid receptor isoforms utilize distinct mechanisms to regulate ERK 1/2 activation. Biochim Biophys Acta. 2009; 1791(4):238-45. PMC: 2679851. DOI: 10.1016/j.bbalip.2009.01.021. View

Acevedo J, Centanin L, Dekanty A, Wappner P . Oxygen sensing in Drosophila: multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFalpha/Sima. PLoS One. 2010; 5(8):e12390. PMC: 2928329. DOI: 10.1371/journal.pone.0012390. View

Ma X, Kawamoto S, Uribe J, Adelstein R . Function of the neuron-specific alternatively spliced isoforms of nonmuscle myosin II-B during mouse brain development. Mol Biol Cell. 2006; 17(5):2138-49. PMC: 1446101. DOI: 10.1091/mbc.e05-10-0997. View

Bastos E, Avila S, Cravador A, Renaville R, Guedes-Pinto H, Castrillo J . Identification and characterization of four splicing variants of ovine POU1F1 gene. Gene. 2006; 382:12-9. DOI: 10.1016/j.gene.2006.05.028. View

10.

Tsai K, Tseng H, Lin W . Two wobble-splicing events affect ING4 protein subnuclear localization and degradation. Exp Cell Res. 2008; 314(17):3130-41. DOI: 10.1016/j.yexcr.2008.08.002. View

11.

Chen M, Ma S, Dumitrache L, Hasty P . Biochemical and cellular characteristics of the 3' -> 5' exonuclease TREX2. Nucleic Acids Res. 2007; 35(8):2682-94. PMC: 1885668. DOI: 10.1093/nar/gkm151. View

12.

Tazi J, Bakkour N, Marchand V, Ayadi L, Aboufirassi A, Branlant C . Alternative splicing: regulation of HIV-1 multiplication as a target for therapeutic action. FEBS J. 2010; 277(4):867-76. DOI: 10.1111/j.1742-4658.2009.07522.x. View

13.

Nern A, Nguyen L, Herman T, Prakash S, Clandinin T, Zipursky S . An isoform-specific allele of Drosophila N-cadherin disrupts a late step of R7 targeting. Proc Natl Acad Sci U S A. 2005; 102(36):12944-9. PMC: 1192823. DOI: 10.1073/pnas.0502888102. View

14.

Woolfe A, Mullikin J, Elnitski L . Genomic features defining exonic variants that modulate splicing. Genome Biol. 2010; 11(2):R20. PMC: 2872880. DOI: 10.1186/gb-2010-11-2-r20. View

15.

Ren S, Nguyen L, Wu S, Encinas C, Adams J, Hewison M . Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis. J Biol Chem. 2005; 280(21):20604-11. DOI: 10.1074/jbc.M414522200. View

16.

Wu Y, Lu Y, Hu Y, Li R . Cyclic AMP-dependent modification of gonad-selective TAF(II)105 in a human ovarian granulosa cell line. J Cell Biochem. 2005; 96(4):751-9. DOI: 10.1002/jcb.20577. View

17.

Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D . Function of alternative splicing. Gene. 2005; 344:1-20. DOI: 10.1016/j.gene.2004.10.022. View

18.

Xu Q, Lee C . Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res. 2003; 31(19):5635-43. PMC: 206480. DOI: 10.1093/nar/gkg786. View

19.

Osuka F, Endo Y, Higuchi M, Suzuki H, Shio Y, Fujiu K . Molecular cloning and characterization of novel splicing variants of human decay-accelerating factor. Genomics. 2006; 88(3):316-22. DOI: 10.1016/j.ygeno.2006.01.006. View

20.

Zhang P, Takeuchi K, Csaki L, Reue K . Lipin-1 phosphatidic phosphatase activity modulates phosphatidate levels to promote peroxisome proliferator-activated receptor γ (PPARγ) gene expression during adipogenesis. J Biol Chem. 2011; 287(5):3485-94. PMC: 3271002. DOI: 10.1074/jbc.M111.296681. View