PMID- 33843145 OWN - NLM STAT- MEDLINE DCOM- 20211210 LR - 20220114 IS - 1757-7012 (Electronic) IS - 1757-7004 (Linking) VI - 12 IP - 5 DP - 2021 Sep TI - On the function and relevance of alternative 3'-UTRs in gene expression regulation. PG - e1653 LID - 10.1002/wrna.1653 [doi] AB - Messanger RNA (mRNA) isoforms with alternative 3'-untranslated regions (3'-UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type- and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3'-UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell. Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3'-UTR profiles are associated with particular cellular states and diseases. Generally, short 3'-UTRs are associated with proliferative and cancer cells, and long 3'-UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3'-UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools. This article is categorized under: RNA Processing > 3' End Processing RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease. CI - (c) 2021 Wiley Periodicals LLC. FAU - Pereira-Castro, Isabel AU - Pereira-Castro I AUID- ORCID: 0000-0003-4149-4310 AD - Gene Regulation, i3S, Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Porto, Portugal. AD - IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. FAU - Moreira, Alexandra AU - Moreira A AUID- ORCID: 0000-0001-9853-7575 AD - Gene Regulation, i3S, Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Porto, Portugal. AD - IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. AD - ICBAS, Instituto de Ciencias Biomedicas Abel Salazar, Universidade do Porto, Porto, Portugal. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20210412 PL - United States TA - Wiley Interdiscip Rev RNA JT - Wiley interdisciplinary reviews. RNA JID - 101536955 RN - 0 (3' Untranslated Regions) RN - 0 (RNA, Messenger) RN - 0 (RNA-Binding Proteins) SB - IM EIN - Wiley Interdiscip Rev RNA. 2022 Jan;13(1):e1706. PMID: 35029331 MH - 3' Untranslated Regions MH - *Gene Expression Regulation MH - *Polyadenylation MH - RNA, Messenger/metabolism MH - RNA-Binding Proteins/metabolism EDAT- 2021/04/13 06:00 MHDA- 2021/12/15 06:00 CRDT- 2021/04/12 06:41 PHST- 2021/03/15 00:00 [revised] PHST- 2021/01/05 00:00 [received] PHST- 2021/03/16 00:00 [accepted] PHST- 2021/04/13 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/04/12 06:41 [entrez] AID - 10.1002/wrna.1653 [doi] PST - ppublish SO - Wiley Interdiscip Rev RNA. 2021 Sep;12(5):e1653. doi: 10.1002/wrna.1653. Epub 2021 Apr 12.