Endocrinol Metab.  2017 Dec;32(4):413-421. 10.3803/EnM.2017.32.4.413.

Alternative Polyadenylation in Human Diseases

Affiliations
  • 1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities College of Biological Sciences, Minneapolis, MN, USA. jyong@umn.edu

Abstract

Varying length of messenger RNA (mRNA) 3"²-untranslated region is generated by alternating the usage of polyadenylation sites during pre-mRNA processing. It is prevalent through all eukaryotes and has emerged as a key mechanism for controlling gene expression. Alternative polyadenylation (APA) plays an important role for cell growth, proliferation, and differentiation. In this review, we discuss the functions of APA related with various physiological conditions including cellular metabolism, mRNA processing, and protein diversity in a variety of disease models. We also discuss the molecular mechanisms underlying APA regulation, such as variations in the concentration of mRNA processing factors and RNA-binding proteins, as well as global transcriptome changes under cellular signaling pathway.

Keyword

Polyadenylation; 3′ Untranslated regions; TOR serine-threonine kinases; RNA 3′ end processing

MeSH Terms

Eukaryota
Gene Expression
Humans*
Metabolism
Polyadenylation*
RNA Precursors
RNA, Messenger
RNA-Binding Proteins
TOR Serine-Threonine Kinases
Transcriptome
RNA Precursors
RNA, Messenger
RNA-Binding Proteins
TOR Serine-Threonine Kinases

Figure

  • Fig. 1 (A) 3′-End processing complexes and cis-acting elements of the 3′-last exon for polyadenylation. RNA polymerase II C-terminal domain (CTD) is associated with many 3′-end processing proteins. The combination of upstream sequence elements (USE), downstream sequence element (DSE), and polyadenylation signal (PAS) is used to determine the cleavage site of a transcript during transcription termination. (B) Alternative polyadenylation (APA) and its effect on protein production. In 3′-untranslated region (UTR) APA, the usage of proximal PAS can be increased or decreased by cleavage stimulation factor (CSFT) 2 or cleavage and polyadenylation specificity factor (CPSF) 5/6 respectively. The length of 3′-UTR could affect the interaction with microRNA (miRNAs) or RNA-binding proteins (RBPs) and modulate protein synthesis. APA in intron regions could affect the coding capacity of protein and thus produce truncated protein. CF, cleavage factor; PCF11, PCF11 cleavage and polyadenylation factor subunit; CLP1, cleavage and polyadenylation factor I subunit 1; WDR33, WD repeat domain 33; FIP1L1, factor interacting with PAPOLA and CPSF1; ATG, initiation codon; TAA, termination codon; TSS, transcription start site.


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