A conserved role for the zinc finger polyadenosine RNA binding protein, ZC3H14, in control of poly(A) tail length

Kelly, Seth M.; Leung, Sara W.; Pak, ChangHui; Banerjee, Ayan; Moberg, Kenneth H.; Corbett, Anita H.

doi:10.1261/rna.043984.113

Cited by 62 publications

(120 citation statements)

References 34 publications

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“…The functions of Nab2 homologs in these diverse organisms also seem to be conserved: Poly(A) binding has been shown in H. sapiens, M. musculus, R. norvegicus, and D. melanogaster (Pak et al 2011;Kelly et al 2014), and its requirement for correct poly(A) tail length has been shown in D. melanogaster and probably H. sapiens (Pak et al 2011). Human ZC3H14 is ubiquitously expressed and exists in four different splice variants: Isoforms 1, 2, 3, and 3short contain a predicted classical nuclear localization signal (cNLS) and localize to the nucleus, whereas isoform 4 contains an alternative first exon lacking the NLS and consequently localizes to the cytoplasm (Leung et al 2009).…”

Section: Discussionmentioning

confidence: 99%

The poly(A)-binding protein Nab2 functions in RNA polymerase III transcription

2015

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RNA polymerase III (RNAPIII) synthesizes most small RNAs, the most prominent being tRNAs. Although the basic mechanism of RNAPIII transcription is well understood, recent evidence suggests that additional proteins play a role in RNAPIII transcription. Here, we discovered by a genome-wide approach that Nab2, a poly(A)-binding protein important for correct poly(A) tail length and nuclear mRNA export, is present at all RNAPIII transcribed genes. The occupancy of Nab2 at RNAPIII transcribed genes is dependent on transcription. Using a novel temperature-sensitive allele of NAB2, nab2-34, we show that Nab2 is required for the occupancy of RNAPIII and TFIIIB at target genes. Furthermore, Nab2 interacts with RNAPIII, TFIIIB, and RNAPIII transcripts. Importantly, impairment of Nab2 function causes an RNAPIII transcription defect in vivo and in vitro. Taken together, we establish Nab2, an important mRNA biogenesis factor, as a novel player required for RNAPIII transcription by stabilizing TFIIIB and RNAPIII at promoters.[Keywords: RNA polymerase III; Nab2; tRNA; ncRNA; gene expression; TFIIIB] Supplemental material is available for this article. RNA polymerase III (RNAPIII) is responsible for the production of most noncoding RNAs (ncRNAs) such as tRNAs, the 5S rRNA (encoded by RDN5), the RNA of the signal recognition particle (SCR1), the spliceosomal U6 snRNA (SNR6), and the RNA component of RNase P (RPR1). Transcription by RNAPIII is initiated at three classes of promoters, which are highly diverse, have a relatively small number of cis-acting elements, and require comparably few transcription factors (TFs) (White 2011;Orioli et al. 2012;Acker et al. 2013 and references therein). Type 1 promoters are exclusively present at 5S rRNA-encoding genes (RN5S in mammals, and RDN5 in yeast). Type 1 promoters have three internal elements: the A box, which is recognized by TFIIIC, and the intermediate element (IE) and the C box, which are recognized by TFIIIA. The most common RNAPIII promoters are of type 2 and drive transcription of tRNA genes as well as, e.g., the SCR1 and RPR1 genes. Type 2 promoters consist of A-and B-box elements, which together recruit TFIIIC. TFIIIC recruits TFIIIB to the transcription start site at type 1 and type 2 promoters. Type 3 promoters are relatively rare, and, in contrast to type 1 and 2 promoters, all of their elements lie 5 ′ of the transcription start site: the distal sequence element (DSE), the proximal sequence element (PSE), and the TATA box. The DSE recruits the TFs Oct1 and STAF, whereas the PSE recruits SNAP c , which in turn binds TFIIIB and recruits it together with the TATA box to the promoter (Schramm and Hernandez 2002 and references therein). Type 3 promoters are only present in vertebrates; e.g., at the U6 snRNA gene. The promoter of the Saccharomyces cerevisiae U6 snRNA gene SNR6 is of type 2 and contains an upstream TATA box in addition to the canonical A and B boxes (Brow and Guthrie 1990;Eschenlauer et al. 1993). At all three types of promoters, TFIIIB recruits RNAPIII. TFIIIB i...

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Section: Discussionmentioning

confidence: 99%

The poly(A)-binding protein Nab2 functions in RNA polymerase III transcription

2015

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“…Recent work on D. melanogaster Nab2 (dNab2) provides evidence for the critical role of this protein in neurons. Re-expression of dNab2 specifically in the neurons of dNab2 null flies rescues developmental and locomotor defects observed in these mutant flies (12,31). Importantly, in a trans-species rescue experiment, the nuclear isoform of ZC3H14, isoform 1, but not the cytoplasmic isoform 4, can also rescue dNab2 mutant phenotypes, providing evidence for the critical function of ZC3H14 in neurons (12,31).…”

Section: Zc3h14 Ensures Proper Processing Of Atp5g1 Pre-mrnamentioning

confidence: 80%

“…Extensive biochemical studies demonstrate that ZC3H14/ Nab2 binds polyadenosine RNA with high affinity (15) and plays an evolutionarily conserved role in poly(A) tail length regulation (12,24,31), supporting a model where ZC3H14 likely binds to the poly(A) tails added to virtually all mRNA transcripts. However, the results from our microarray analysis suggest that ZC3H14 could regulate specific mRNA targets in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 92%

“…Re-expression of dNab2 specifically in the neurons of dNab2 null flies rescues developmental and locomotor defects observed in these mutant flies (12,31). Importantly, in a trans-species rescue experiment, the nuclear isoform of ZC3H14, isoform 1, but not the cytoplasmic isoform 4, can also rescue dNab2 mutant phenotypes, providing evidence for the critical function of ZC3H14 in neurons (12,31). The fractionation studies presented here as well as rescue of fly phenotypes by nuclear ZC3H14 are consistent with the model where ZC3H14 is critical for proper maturation of specific target mRNAs within the nucleus.…”

Section: Zc3h14 Ensures Proper Processing Of Atp5g1 Pre-mrnamentioning

confidence: 98%

“…Extensive work on the Saccharomyces cerevisiae ortholog of ZC3H14, Nab2 (22,23), reveals that this essential protein plays roles in poly(A) tail length control and mRNA export (24 -27), target transcript stability (28), and RNA quality control in the nucleus (29,30). Genetic analyses performed in Drosophila melanogaster reveal a conserved function of Drosophila Nab2 (dNab2) in post-transcriptional processing, specifically in neurons (31), consistent with the brain dysfunction present in patients. Understanding the role of ZC3H14 in human cells is not only critical to determine the molecular basis for the observed neuronal phenotype in patients but also to integrate the function of ZC3H14 into our current understanding of the Pab family of proteins.…”

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confidence: 96%

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The Polyadenosine RNA-binding Protein, Zinc Finger Cys3His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA

Wigington

Morris

Newman

et al. 2016

Journal of Biological Chemistry

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Polyadenosine RNA-binding proteins (Pabs) regulate multiple steps in gene expression. This protein family includes the well studied Pabs, PABPN1 and PABPC1, as well as the newly characterized Pab, zinc finger CCCH-type containing protein 14 (ZC3H14). Mutations in ZC3H14 are linked to a form of intellectual disability. To probe the function of ZC3H14, we performed a transcriptome-wide analysis of cells depleted of either ZC3H14 or the control Pab, PABPN1. Depletion of PABPN1 affected ϳ17% of expressed transcripts, whereas ZC3H14 affected only ϳ1% of expressed transcripts. To assess the function of ZC3H14 in modulating target mRNAs, we selected the gene encoding the ATP synthase F 0 subunit C (ATP5G1) transcript. Knockdown of ZC3H14 significantly reduced ATP5G1 steady-state mRNA levels. Consistent with results suggesting that ATP5G1 turnover increases upon depletion of ZC3H14, double knockdown of ZC3H14 and the nonsense-mediated decay factor, UPF1, rescues ATP5G1 transcript levels. Furthermore, fractionation reveals an increase in the amount of ATP5G1 pre-mRNA that reaches the cytoplasm when ZC3H14 is depleted and that ZC3H14 binds to ATP5G1 pre-mRNA in the nucleus. These data support a role for ZC3H14 in ensuring proper nuclear processing and retention of ATP5G1 pre-mRNA. Consistent with the observation that ATP5G1 is a rate-limiting component for ATP synthase activity, knockdown of ZC3H14 decreases cellular ATP levels and causes mitochondrial fragmentation. These data suggest that ZC3H14 modulates pre-mRNA processing of select mRNA transcripts and plays a critical role in regulating cellular energy levels, observations that have broad implications for proper neuronal function.

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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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A conserved role for the zinc finger polyadenosine RNA binding protein, ZC3H14, in control of poly(A) tail length

Cited by 62 publications

References 34 publications

The poly(A)-binding protein Nab2 functions in RNA polymerase III transcription

The poly(A)-binding protein Nab2 functions in RNA polymerase III transcription

The Polyadenosine RNA-binding Protein, Zinc Finger Cys3His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA

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

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