Nucleophosmin deposition during mRNA 3′ end processing influences poly(A) tail length

Sagawa, Fumihiko; Ibrahim, Hend; Morrison, Angela L; Wilusz, Carol J.; Wilusz, Jeffrey

doi:10.1038/emboj.2011.272

Cited by 32 publications

(29 citation statements)

References 55 publications

(98 reference statements)

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“…The mRNAs appear to be degraded during or immediately after nuclear export. Presumably, these mRNAs are targeted for rapid degradation because of a lack of cleavage, an incomplete poly(A) tail, or a lack of deposition of nucleophosmin on the 39 end of the mRNA (Yen et al 2004;Martick et al 2008;Meaux et al 2011;Sagawa et al 2011). A fundamental difference between the inflammatory messenger ribonucleoprotein complexes (mRNPs) and the RPL10A mRNP must exist that exempts RPL10A mRNA from this degradation pathway, as the effects on termination and cleavage are similar for RPL10A and CXCL1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of polyadenylation reduces inflammatory gene induction

Kondrashov

Meijer

Barthet-Barateig

et al. 2012

RNA

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Cordycepin (39 deoxyadenosine) has long been used in the study of in vitro assembled polyadenylation complexes, because it terminates the poly(A) tail and arrests the cleavage complex. It is derived from caterpillar fungi, which are highly prized in Chinese traditional medicine. Here we show that cordycepin specifically inhibits the induction of inflammatory mRNAs by cytokines in human airway smooth muscle cells without affecting the expression of control mRNAs. Cordycepin treatment results in shorter poly(A) tails, and a reduction in the efficiency of mRNA cleavage and transcription termination is observed, indicating that the effects of cordycepin on 39 processing in cells are similar to those described in in vitro reactions. For the CCL2 and CXCL1 mRNAs, the effects of cordycepin are post-transcriptional, with the mRNA disappearing during or immediately after nuclear export. In contrast, although the recruitment of RNA polymerase II to the IL8 promoter is also unaffected, the levels of nascent transcript are reduced, indicating a defect in transcription elongation. We show that a reporter construct with 39 sequences from a histone gene is unaffected by cordycepin, while CXCL1 sequences confer cordycepin sensitivity to the reporter, demonstrating that polyadenylation is indeed required for the effect of cordycepin on gene expression. In addition, treatment with another polyadenyation inhibitor and knockdown of poly(A) polymerase a also specifically reduced the induction of inflammatory mRNAs. These data demonstrate that there are differences in the 39 processing of inflammatory and housekeeping genes and identify polyadenylation as a novel target for anti-inflammatory drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of polyadenylation reduces inflammatory gene induction

Kondrashov

Meijer

Barthet-Barateig

et al. 2012

RNA

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“…First, during the termination steps of polyadenylation, nucleophosmin (NPM1 or B23) is deposited on the 3′UTR of the transcript near the PAS [81]. NPM1 interacts with the core CPSF complex in an RNA-independent fashion [82]. Interestingly, NPM1 deposition appears to play a significant role in regulating proper poly(A) tail length, as knocking down NPM1 leads to hyperadenylation and nuclear accumulation of mRNAs [82].…”

Section: Nuclear Factors That Regulate the Poly(a) Tailmentioning

confidence: 99%

“…NPM1 interacts with the core CPSF complex in an RNA-independent fashion [82]. Interestingly, NPM1 deposition appears to play a significant role in regulating proper poly(A) tail length, as knocking down NPM1 leads to hyperadenylation and nuclear accumulation of mRNAs [82]. Thus NPM1 has been postulated to serve as a mark for transcripts that have been properly polyadenylated.…”

Section: Nuclear Factors That Regulate the Poly(a) Tailmentioning

confidence: 99%

“…One model suggests that Nab2/ZC3H14 restricts PAP activity and that it may also recruit ribonucleases to trim excess A-residues [83]. Nab2/ZC3H14 , NPM1 and PABPN1 remain bound at or near the poly(A) tail and assist in the translocation of mRNAs from the nucleus to cytoplasm where transcripts interact with multiple other factors to become primed for translation [79,82,84]. …”

Section: Nuclear Factors That Regulate the Poly(a) Tailmentioning

confidence: 99%

“…A key point in understanding poly(A) tail dynamics, however, is that bigger is not always better. Hyperadenylation, as seen in viral infection or NPM-1 depletion, leads to nuclear retention of mRNAs, which would reduce the ability of these mRNAs to be translated and could have other negative effects on nuclear activity [10,11,78,82]. Hyperadenylation is also associated with increased mRNA turnover rates [10].…”

Section: Some Final Thoughts On the Dynamics Of Poly(a) Tail Sizementioning

confidence: 99%

See 2 more Smart Citations

Determinants and implications of mRNA poly(A) tail size – Does this protein make my tail look big?

Jalkanen

Coleman

Wilusz

2014

Seminars in Cell & Developmental Biology

Self Cite

118

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While the phenomenon of polyadenylation has been well-studied, the dynamics of poly(A) tail size and its impact on transcript function and cell biology are less well-appreciated. The goal of this review is to encourage readers to view the poly(A) tail as a dynamic, changeable aspect of a transcript rather than a simple static entity that marks the 3′ end of an mRNA. This could open up new angles of regulation in the post-transcriptional control of gene expression throughout development, differentiation and cancer.

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Birth of a poly(A) tail: mechanisms and control of mRNA polyadenylation

Rodríguez-Molina

Turtola

2022

FEBS Open Bio

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During their synthesis in the cell nucleus, most eukaryotic mRNAs undergo a two‐step 3′‐end processing reaction in which the pre‐mRNA is cleaved and released from the transcribing RNA polymerase II and a polyadenosine (poly(A)) tail is added to the newly formed 3′‐end. These biochemical reactions might appear simple at first sight (endonucleolytic RNA cleavage and synthesis of a homopolymeric tail), but their catalysis requires a multi‐faceted enzymatic machinery, the cleavage and polyadenylation complex (CPAC), which is composed of more than 20 individual protein subunits. The activity of CPAC is further orchestrated by Poly(A) Binding Proteins (PABPs), which decorate the poly(A) tail during its synthesis and guide the mRNA through subsequent gene expression steps. Here, we review the structure, molecular mechanism, and regulation of eukaryotic mRNA 3′‐end processing machineries with a focus on the polyadenylation step. We concentrate on the CPAC and PABPs from mammals and the budding yeast, Saccharomyces cerevisiae, because these systems are the best‐characterized at present. Comparison of their functions provides valuable insights into the principles of mRNA 3′‐end processing.

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Nucleophosmin deposition during mRNA 3′ end processing influences poly(A) tail length

Cited by 32 publications

References 55 publications

Inhibition of polyadenylation reduces inflammatory gene induction

Inhibition of polyadenylation reduces inflammatory gene induction

Determinants and implications of mRNA poly(A) tail size – Does this protein make my tail look big?

Birth of a poly(A) tail: mechanisms and control of mRNA polyadenylation

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