Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression

Passmore, Lori A.; Coller, Jeff

doi:10.1038/s41580-021-00417-y

Cited by 249 publications

(256 citation statements)

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“…During this latter process, a cleavage event defines the 3′ end of the mature mRNA and is linked to transcription termination ( Buratowski 2005 ; Liu and Moore 2021 ). A poly(A) tail is added to the resultant free 3′ end, marking the mRNA for nuclear export and controlling mRNA stability and translational efficiency in the cytoplasm ( Passmore and Coller 2022 ). Thus, 3′ cleavage and polyadenylation are critical to the production of functional protein-coding transcripts.…”

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confidence: 99%

RBBP6 activates the pre-mRNA 3′ end processing machinery in humans

et al. 2022

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3′ end processing of most human mRNAs is carried out by the cleavage and polyadenylation specificity factor (CPSF; CPF in yeast). Endonucleolytic cleavage of the nascent pre-mRNA defines the 3′ end of the mature transcript, which is important for mRNA localization, translation, and stability. Cleavage must therefore be tightly regulated. Here, we reconstituted specific and efficient 3′ endonuclease activity of human CPSF with purified proteins. This required the seven-subunit CPSF as well as three additional protein factors: cleavage stimulatory factor (CStF), cleavage factor IIm (CFIIm), and, importantly, the multidomain protein RBBP6. Unlike its yeast homolog Mpe1, which is a stable subunit of CPF, RBBP6 does not copurify with CPSF and is recruited in an RNA-dependent manner. Sequence and mutational analyses suggest that RBBP6 interacts with the WDR33 and CPSF73 subunits of CPSF. Thus, it is likely that the role of RBBP6 is conserved from yeast to humans. Overall, our data are consistent with CPSF endonuclease activation and site-specific pre-mRNA cleavage being highly controlled to maintain fidelity in mRNA processing.

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confidence: 99%

RBBP6 activates the pre-mRNA 3′ end processing machinery in humans

et al. 2022

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“…Transcripts with very short polyA tails are associated with both inefficient translation and low stability (36). We used an in-house script to identify RSV transcripts from each time point which had short polyA tail lengths (<=20 nt) that nanopolish determined was suitable to estimate a poly A tail length for.…”

Section: Resultsmentioning

confidence: 99%

Direct RNA sequencing of Respiratory Syncytial Virus infected human cells generates a detailed overview of RSV polycistronic mRNA and transcript abundance

Banfield

Hall

Gao

et al. 2021

Preprint

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To characterize species of viral mRNA transcripts generated during respiratory syncytial virus (RSV) infection, human fibroblast-like MRC5 lung cells were infected with subgroup A RSV for 6, 16 and 24 hours. Total RNA was harvested and polyadenylated mRNA was enriched and sequenced by direct RNA sequencing on an Oxford nanopore device. This yielded over 150,000 direct mRNA transcript reads which were mapped to the viral genome and analysed to determine relative mRNA levels of viral genes using our in-house ORF-centric pipeline. We were also able to examine frequencies with which polycistronic readthrough mRNAs were generated and to assess the length of the polyadenylated tails for each group of transcripts. We show that there is a general but non-linear decline in gene transcript abundance across the viral genome, as predicted by the model of RSV gene transcription. However, the decline in transcript abundance is not consistent. We show that the polyadenylate tails generated by the viral polymerase are similar in length to those generated by the host cells polyadenylation machinery and broadly declined in length for most transcripts as infection progressed. Finally, we observed that the steady state abundance of transcripts with very short polyadenylate tails is much less for N, SH and G transcripts compared to NS1, NS2, P, M, F and M2 which may reflect differences in mRNA stability and/or translation rates.

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“…The poly(A) tail plays an important role in a transcript’s life cycle [ 2 ]. For example, it is responsible for mediating the transport of mature mRNA into the cytoplasm through the NXF1-dependent pathway using nuclear-pore complexes embedded in the nuclear envelope [ 14 ].…”

Section: Polyadenylation In Animal Cellsmentioning

confidence: 99%

“…There is a great need for the precise, molecular characterization of transcript variants to understand cell-type-specific processes and their disruption in cases of gene mutations. This includes aspects of poly(A) tail processing, which is especially crucial in neuronal cells, as features of the 3′ end of an mRNA play an important role in regulating the dynamics of RNA metabolism and translation [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Joachimiak

Ciesiolka

Figura

et al. 2022

Cells

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Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies.

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Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression

Cited by 249 publications

References 200 publications

RBBP6 activates the pre-mRNA 3′ end processing machinery in humans

RBBP6 activates the pre-mRNA 3′ end processing machinery in humans

Direct RNA sequencing of Respiratory Syncytial Virus infected human cells generates a detailed overview of RSV polycistronic mRNA and transcript abundance

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

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