Alternative mRNA polyadenylation in eukaryotes: an effective regulator of gene expression

Lutz, Carol S.; Moreira, Alexandra

doi:10.1002/wrna.47

Cited by 130 publications

(117 citation statements)

References 70 publications

(107 reference statements)

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Since mRNA 39-end processing occurs cotranscriptionally and is stimulated by Pol II CTD (Proudfoot 2004), it is clear that once a particular PAS has been selected and mRNA 39 cleavage occurs with consequent release from chromatin-associated Pol II, then further cleavage of more proximal PAS on the mRNA will not occur. Thus, mRNAs with extended 39 UTRs are carried through into the cytoplasm, where particular 39 UTR sequences act to regulate both the stability and translatability of mRNA as described below (for a recent review on APA, see Lutz and Moreira 2011).…”

Section: Alternative Pas (Apa) Define Different Mrna 39 Utrsmentioning

confidence: 99%

Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

501

477

View full text Add to dashboard Cite

Polyadenylation [poly(A)] signals (PAS) are a defining feature of eukaryotic protein-coding genes. The central sequence motif AAUAAA was identified in the mid1970s and subsequently shown to require flanking, auxiliary elements for both 39-end cleavage and polyadenylation of premessenger RNA (pre-mRNA) as well as to promote downstream transcriptional termination. More recent genomic analysis has established the generality of the PAS for eukaryotic mRNA. Evidence for the mechanism of mRNA 39-end formation is outlined, as is the way this RNA processing reaction communicates with RNA polymerase II to terminate transcription. The widespread phenomenon of alternative poly(A) site usage and how this interrelates with pre-mRNA splicing is then reviewed. This shows that gene expression can be drastically affected by how the message is ended. A central theme of this review is that while genomic analysis provides generality for the importance of PAS selection, detailed mechanistic understanding still requires the direct analysis of specific genes by genetic and biochemical approaches.

show abstract

Section: Alternative Pas (Apa) Define Different Mrna 39 Utrsmentioning

confidence: 99%

Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

501

477

View full text Add to dashboard Cite

show abstract

“…During normal development and in the progression of diseases such as cancer, 39 end cleavage site usage frequently changes, resulting in additional sequence motifs being included (or excluded) at the 39 ends of mature RNAs that can affect the transcripts' stability, subcellular localization, or function (for review, see Lutz and Moreira 2011). Virtually all long RNA polymerase II (Pol II) transcripts terminate in a poly(A) tail that is generated by endonucleolytic cleavage followed by the addition of adenosine (A) residues in a nontemplated fashion (Moore and Sharp 1985; for review, see Colgan and Manley 1997;Zhao et al 1999;Proudfoot 2004).…”

mentioning

confidence: 99%

A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails

et al. 2012

View full text Add to dashboard Cite

The MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) locus is misregulated in many human cancers and produces an abundant long nuclear-retained noncoding RNA. Despite being transcribed by RNA polymerase II, the 39 end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of a tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail yet is expressed at a level higher than many protein-coding genes in vivo. Here we show that the 39 ends of MALAT1 and the MEN b long noncoding RNAs are protected from 39-59 exonucleases by highly conserved triple helical structures. Surprisingly, when these structures are placed downstream from an ORF, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. The triple helix therefore also functions as a translational enhancer, and mutations in this region separate this translation activity from simple effects on RNA stability or transport. We further found that a transcript ending in a triple helix is efficiently repressed by microRNAs in vivo, arguing against a major role for the poly(A) tail in microRNA-mediated silencing. These results provide new insights into how transcripts that lack poly(A) tails are stabilized and regulated and suggest that RNA triple-helical structures likely have key regulatory functions in vivo.

show abstract

“…Alternating the usage of PAS, namely alternative cleavage and polyadenylation (ApA), produces mRNA isoforms with the same coding capacity but with various lengths of 3 0 -UTR [1][2][3][4] . As 3 0 -UTR provides a binding platform for microRNAs and RNA-binding proteins, it serves as an important determinant for mRNA fate such as translation and stability 2,3,5,6 . Therefore, ApA provides an additional layer of complexity in regulating gene expression at the posttranscriptional level.…”

mentioning

confidence: 99%