3'UTR Diversity: Expanding Repertoire of RNA Alterations in Human MRNAs

Overview

Journal Mol Cells

Publisher Elsevier

Specialties Cell Biology
Molecular Biology

Date 2023 Jan 25

PMID 36697237

Authors

Dawon Hong

Sunjoo Jeong

Affiliations

Soon will be listed here.

Abstract

Genomic information stored in the DNA is transcribed to the mRNA and translated to proteins. The 3' untranslated regions (3'UTRs) of the mRNA serve pivotal roles in posttranscriptional gene expression, regulating mRNA stability, translation, and localization. Similar to DNA mutations producing aberrant proteins, RNA alterations expand the transcriptome landscape and change the cellular proteome. Recent global analyses reveal that many genes express various forms of altered RNAs, including 3'UTR length variants. Alternative polyadenylation and alternative splicing are involved in diversifying 3'UTRs, which could act as a hidden layer of eukaryotic gene expression control. In this review, we summarize the functions and regulations of 3'UTRs and elaborate on the generation and functional consequences of 3'UTR diversity. Given that dynamic 3'UTR length control contributes to phenotypic complexity, dysregulated 3'UTR diversity might be relevant to disease development, including cancers. Thus, 3'UTR diversity in cancer could open exciting new research areas and provide avenues for novel cancer theragnostics.

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References

Marini F, Scherzinger D, Danckwardt S . TREND-DB-a transcriptome-wide atlas of the dynamic landscape of alternative polyadenylation. Nucleic Acids Res. 2020; 49(D1):D243-D253. PMC: 7778938. DOI: 10.1093/nar/gkaa722. View

Bicknell A, Cenik C, Chua H, Roth F, Moore M . Introns in UTRs: why we should stop ignoring them. Bioessays. 2012; 34(12):1025-34. DOI: 10.1002/bies.201200073. View

Giles K, Daly J, Beveridge D, Thomson A, Voon D, Furneaux H . The 3'-untranslated region of p21WAF1 mRNA is a composite cis-acting sequence bound by RNA-binding proteins from breast cancer cells, including HuR and poly(C)-binding protein. J Biol Chem. 2002; 278(5):2937-46. DOI: 10.1074/jbc.M208439200. View

Navarro E, Mallen A, Hueso M . Dynamic Variations of 3'UTR Length Reprogram the mRNA Regulatory Landscape. Biomedicines. 2021; 9(11). PMC: 8615635. DOI: 10.3390/biomedicines9111560. View

Tian B, Manley J . Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci. 2013; 38(6):312-20. PMC: 3800139. DOI: 10.1016/j.tibs.2013.03.005. View

Griesemer D, Xue J, Reilly S, Ulirsch J, Kukreja K, Davis J . Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution. Cell. 2021; 184(20):5247-5260.e19. PMC: 8487971. DOI: 10.1016/j.cell.2021.08.025. View

Lai W, Carballo E, Strum J, Kennington E, Phillips R, Blackshear P . Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol. 1999; 19(6):4311-23. PMC: 104391. DOI: 10.1128/MCB.19.6.4311. View

Vernet C, Artzt K . STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet. 1998; 13(12):479-84. DOI: 10.1016/s0168-9525(97)01269-9. View

Nam J, Rissland O, Koppstein D, Abreu-Goodger C, Jan C, Agarwal V . Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell. 2014; 53(6):1031-1043. PMC: 4062300. DOI: 10.1016/j.molcel.2014.02.013. View

10.

Jafarifar F, Yao P, Eswarappa S, Fox P . Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L. EMBO J. 2011; 30(7):1324-34. PMC: 3094116. DOI: 10.1038/emboj.2011.38. View

11.

Kim J, Park R, Kee Y, Jeong S, Ohn T . Splicing factor SRSF3 represses translation of p21 mRNA. Cell Death Dis. 2022; 13(11):933. PMC: 9640673. DOI: 10.1038/s41419-022-05371-x. View

12.

Hoque M, Ji Z, Zheng D, Luo W, Li W, You B . Analysis of alternative cleavage and polyadenylation by 3' region extraction and deep sequencing. Nat Methods. 2012; 10(2):133-9. PMC: 3560312. DOI: 10.1038/nmeth.2288. View

13.

Reamon-Buettner S, Cho S, Borlak J . Mutations in the 3'-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Med Genet. 2007; 8:38. PMC: 1933416. DOI: 10.1186/1471-2350-8-38. View

14.

Tian S, Curnutte H, Trcek T . RNA Granules: A View from the RNA Perspective. Molecules. 2020; 25(14). PMC: 7397151. DOI: 10.3390/molecules25143130. View

15.

Lee H, Jeong S . Beta-Catenin stabilizes cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3'-UTR. Nucleic Acids Res. 2006; 34(19):5705-14. PMC: 1636482. DOI: 10.1093/nar/gkl698. View

16.

Lorenz R, Bernhart S, Honer Zu Siederdissen C, Tafer H, Flamm C, Stadler P . ViennaRNA Package 2.0. Algorithms Mol Biol. 2011; 6:26. PMC: 3319429. DOI: 10.1186/1748-7188-6-26. View

17.

Wang R, Nambiar R, Zheng D, Tian B . PolyA_DB 3 catalogs cleavage and polyadenylation sites identified by deep sequencing in multiple genomes. Nucleic Acids Res. 2017; 46(D1):D315-D319. PMC: 5753232. DOI: 10.1093/nar/gkx1000. View

18.

Berkovits B, Mayr C . Alternative 3' UTRs act as scaffolds to regulate membrane protein localization. Nature. 2015; 522(7556):363-7. PMC: 4697748. DOI: 10.1038/nature14321. View

19.

Essafi-Benkhadir K, Onesto C, Stebe E, Moroni C, Pages G . Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation. Mol Biol Cell. 2007; 18(11):4648-58. PMC: 2043565. DOI: 10.1091/mbc.e07-06-0570. View

20.

TANEJA K, McCurrach M, Schalling M, Housman D, Singer R . Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol. 1995; 128(6):995-1002. PMC: 2120416. DOI: 10.1083/jcb.128.6.995. View