Alternative polyadenylation in the regulation and dysregulation of gene expression

Turner, Rachael Emily; Pattison, Andrew; Beilharz, Traude H.

doi:10.1016/j.semcdb.2017.08.056

Cited by 54 publications

(52 citation statements)

References 110 publications

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“…Alternative 39-end processing is critical for the regulation of gene expression because this action generates various mRNA isoforms harboring different cis-acting elements. As a consequence, different RNA-binding proteins or noncoding RNAs can be loaded onto the 39 UTR, thereby leading to different gene regulation outcomes (23)(24)(25)(26). Accordingly, the extended 39 UTR of poly(A) + RDH mRNAs should be subject to a mode of gene regulation different from that of canonical SL + RDH mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Eukaryotic gene expression should be tightly regulated to adjust to cellular stresses. In particular, recent data reveal that alternative polyadenylation is affected by cellular stresses, such as cold or heat shock and UV irradiation (23)(24)(25)(26)(39)(40)(41)(42). It is also known that alternative polyadenylation is influenced by treatment with anisomycin, which inhibits the peptidyl transferase activity of a ribosome (43,44).…”

Section: Poly(a) + Rdh Mrnas Are Up-regulated Under Stress Conditionsmentioning

confidence: 99%

“…Therefore, it is plausible that the 39 UTR of poly(A) + RDH mRNA harbors new cis-acting elements and is subject to different regulatory pathways relative to SL + RDH mRNAs. Indeed, recent genome-wide analysis revealed that a significant proportion of mammalian genes contain more than 1 PAS and that 39-end formation accompanying alternative polyadenylation generates mRNA isoforms with alternative 39 ends, which recruit different regulatory factors, such as RNA-binding proteins and noncoding RNAs (23)(24)(25)(26). Accordingly, alternative polyadenylation, and consequently, alternative 39-end formation increase the complexity of the transcriptome, thereby possibly affecting the stability and translation of mRNAs.…”

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confidence: 99%

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HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

et al. 2018

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All metazoan mRNAs have a poly(A) tail at the 3′ end with the exception of replication‐dependent histone (RDH) mRNAs, which end in a highly conserved stem‐loop (SL) structure. However, a subset of RDH mRNAs are reported to be polyadenylated under physiologic conditions. The molecular details of the biogenesis of polyadenylated RDH [poly(A)+ RDH] mRNAs remain unknown. In this study, our genome‐wide analyses reveal that puromycin treatment or UVC irradiation stabilizes poly(A)+ RDH mRNAs, relative to canonical RDH mRNAs, which end in an SL structure. We demonstrate that the stabilization of poly(A)+ RDH mRNAs occurs in a translation‐independent manner and is regulated via human antigen R (HuR) binding to the extended 3′ UTR under stress conditions. Our data suggest that HuR regulates the expression of poly(A)+ RDH mRNAs.—Ryu, I., Park, Y., Seo, J.‐W., Park, O. H., Ha, H., Nam, J.‐W., Kim, Y. K. HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions. FASEB J. 33, 2680–2693 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Section: Poly(a) + Rdh Mrnas Are Up-regulated Under Stress Conditionsmentioning

confidence: 99%

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confidence: 99%

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HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

et al. 2018

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“…Finally, we find a surprising degree of overlap between UPF1 targets and genes previously found to undergo 3'UTR "shortening" in cancer. Multiple lines of evidence suggest that preferential use of proximal pA sites in cancer is associated with increased expression of core cleavage and polyadenylation proteins (Turner et al, 2018), but our data indicate that nuclear control of 3'UTR isoform expression in cancer may be systematically augmented by NMD. These findings raise two possibilities that merit further investigation: first, NMD efficiency may contribute to 3'UTR isoform expression changes in cancer and second, APA may be in part used by cancer cells to evade NMD.…”

Section: Discussionmentioning

confidence: 55%

Activation and inhibition of nonsense-mediated mRNA decay controls the abundance of alternative polyadenylation products

Kishor¹,

Fritz²,

Haque³

et al. 2019

Preprint

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Alternative polyadenylation (APA) produces transcript 3' untranslated regions (3'UTRs) with distinct sequences, lengths, stability, and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3'UTRs that gene-or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3'UTR products of APA, leading to their systematic downregulation. Further, we find that many APA events consistently observed in multiple tumor types are controlled by NMD. Additionally, PTBP1, previously implicated in direct modulation of co-transcriptional polyA site choice, regulates the balance of short and long 3'UTR isoforms by inhibiting NMD. Our data suggest that PTBP1 binding near polyA sites can drive production of long 3'UTR APA products in the nucleus and/or protect them from decay in the cytoplasm. Together, our findings reveal a widespread role for NMD in shaping the outcomes of APA.

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“…The PAT-seq approach identifies polyadenylation sites with exquisite sensitivity, which is confirmed by the high level of overlap with previously annotated positions of 3' UTRs in C. elegans (33) and our wild-type transcriptome (additional Fig 4a). A common idea is that the length of 3' UTR is correlated to the complexity of post-transcriptional regulation (34). Therefore, to ask if the 3' UTRs of GLD-2 target transcripts differ in any global parameters compared to those that are apparently not targeted, we first asked if there was a relationship between 3' UTR length and the change between wild-type and gld-2(0) adenylation state (additional Fig 4b).…”

Section: ' Utr Of Gld-2 Target Mrna Are Longer C-rich and Contain mentioning

confidence: 99%

Widespread cytoplasmic polyadenylation programs asymmetry in the germline and early embryo

Boag

Harrison

Barugahare

et al. 2018

Preprint

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BACKGROUND:The program of embryonic development is launched by selective activation of a silent maternal transcriptome. In Caenorhabditis elegans, nuclei of the adult germline are responsible for the synthesis of at least two distinct mRNA populations; those required for housekeeping functions, and those that program the oocyte-to-embryo transition. We mapped this separation by changes to the length-distribution of poly(A)-tails that depend on GLD-2 mediated cytoplasmic polyadenylation and its regulators genome-wide. RESULTS:More than 1000 targets of cytoplasmic polyadenylation were identified by differential polyadenylation. Amongst mRNA with the greatest dependence on GLD-2 were those encoding RNA binding proteins with known roles in spatiotemporal patterning such as mex-5 and pos-1. In General, the 3' UTR of GLD-2 targets were longer, contained cytosine-patches, and were enriched for non-standard polyadenylation-motifs. To identify the deadenylase that initiated transcript silencing, we depleted the known deadenylases in the gld-2(0) mutant background. Only the loss of CCF-1 suppressed the short-tailed phenotype of GLD-2 targets suggesting that in addition to its general role in RNA turnover, this is the major deadenylase for regulatory silencing of maternal mRNA. Analysis of poly(A)-tail length-change in the embryo lacking specific RNA-binding proteins revealed new candidates for asymmetric expression in the first embryonic divisions. CONCLUSION:The concerted action of RNA binding proteins exquisitely regulates GLD-2 activity in space and time. We present our data as interactive web resources for a model where GLD-2 mediated cytoplasmic polyadenylation regulates target mRNA at each stage of worm germline and early embryonic development.

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Alternative polyadenylation in the regulation and dysregulation of gene expression

Cited by 54 publications

References 110 publications

HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

Activation and inhibition of nonsense-mediated mRNA decay controls the abundance of alternative polyadenylation products

Widespread cytoplasmic polyadenylation programs asymmetry in the germline and early embryo

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