The long and the short of it: The role of the zinc finger polyadenosine RNA binding protein, Nab2, in control of poly(A) tail length

Soucek, Sharon; Corbett, Anita H.; Fasken, Milo B.

doi:10.1016/j.bbagrm.2012.03.006

Cited by 39 publications

(60 citation statements)

References 88 publications

(236 reference statements)

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“…nab2 encodes an essential nuclear protein that harbors seven CCCH ZnF motifs, of which ZnF5 to -7 are necessary and sufficient for high-affinity binding to poly(A) RNA (19,20). Functionally, Nab2 has been implicated in two distinct steps of budding yeast gene expression: mRNA export and poly(A) tail length control (21). Nab2 contributes to the RNA export process by recruiting mRNA export factors (22) and by interacting with nuclear pore-associated proteins (23), interactions that involve a Pro-Trp-Iso (PWI)-like fold located in the amino-terminal region of Nab2 (24).…”

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confidence: 99%

Poly(A) Tail-Mediated Gene Regulation by Opposing Roles of Nab2 and Pab2 Nuclear Poly(A)-Binding Proteins in Pre-mRNA Decay

St-Sauveur

Soucek

Corbett

et al. 2013

Molecular and Cellular Biology

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The 3= end of most eukaryotic transcripts is decorated by poly(A)-binding proteins (PABPs), which influence the fate of mRNAs throughout gene expression. However, despite the fact that multiple PABPs coexist in the nuclei of most eukaryotes, how functional interplay between these nuclear PABPs controls gene expression remains unclear. By characterizing the ortholog of the Nab2/ZC3H14 zinc finger PABP in Schizosaccharomyces pombe, we show here that the two major fission yeast nuclear PABPs, Pab2 and Nab2, have opposing roles in posttranscriptional gene regulation. Notably, we find that Nab2 functions in gene-specific regulation in a manner opposite to that of Pab2. By studying the ribosomal-protein-coding gene rpl30-2, which is negatively regulated by Pab2 via a nuclear pre-mRNA decay pathway that depends on the nuclear exosome subunit Rrp6, we show that Nab2 promotes rpl30-2 expression by acting at the level of the unspliced pre-mRNA. Our data support a model in which Nab2 impedes Pab2/Rrp6-mediated decay by competing with Pab2 for polyadenylated transcripts in the nucleus. The opposing roles of Pab2 and Nab2 reveal that interplay between nuclear PABPs can influence gene regulation. Production of mRNA in eukaryotic cells is a multistep procedure that involves extensive RNA-processing events, such as 5=-end capping, removal of introns by RNA splicing, 3=-end cleavage, and polyadenylation. Polyadenylation has received considerable interest in the past few years, as recent evidence has revealed that polyadenylation can promote RNA turnover in eukaryotic cells (1-5), contrary to the general view that poly(A) tails only contribute positively to gene expression. The extent to which polyadenylation contributes to RNA turnover and the mechanisms that specify this specialized RNA decay pathway remain poorly understood, however.The fundamental role of RNA polyadenylation in gene expression is conferred by the activity of poly(A)-binding proteins (PABPs) that bind to the 3= poly(A) tail of eukaryotic mRNAs. Two evolutionarily conserved RNA recognition motif (RRM)-containing PABPs bind the poly(A) tract of mRNAs in most eukaryotic cells: PABPC1 in the cytoplasm and PABPN1 in the nucleus (6). Biochemical studies on PABPN1 led to a model in which the protein promotes efficient polyadenylation during mRNA synthesis (7). Although a role for PABPN1 in modulating poly(A) tail length is supported by studies in primary mouse myoblasts (8), studies in human cell lines have recently revealed novel functions for PABPN1. One study demonstrated that PABPN1 modulates the use of alternative polyadenylation sites by occluding access to weak polyadenylation signals for a select group of human genes (9, 10). In addition, a recent genome-wide study that addressed the global impact of PABPN1 deficiency on human gene expression uncovered a role for PABPN1 in the negative regulation of long noncoding RNAs (lncRNAs) (11). Interestingly, a 3= poly(A) tail is a prerequisite for PABPN1 to promote lncRNA turnover (11), consistent with a mechanism of ...

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Poly(A) Tail-Mediated Gene Regulation by Opposing Roles of Nab2 and Pab2 Nuclear Poly(A)-Binding Proteins in Pre-mRNA Decay

St-Sauveur

Soucek

Corbett

et al. 2013

Molecular and Cellular Biology

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“…It is present along the whole ORF of protein-coding genes as determined by chromatin immunoprecipitation (ChIP) experiments hybridized to high-density tiling arrays (ChIP-chip) (Meinel et al 2013). As a member of the poly(A)-binding protein (PABP) family, Nab2 binds to the poly(A) tail of mRNAs during or shortly after their polyadenylation, regulating its length (Kelly et al 2010;Soucek et al 2012) and references therein). In addition to poly(A) RNA (Kelly et al 2010), Nab2 also shows nonspecific RNA binding (Kelly et al 2007), consistent with its binding to the body of mRNAs in vivo (Tuck and Tollervey 2013) and its at least partially RNAdependent occupancy at an RNAPII reporter gene (Meinel et al 2013).…”

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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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“…Knockdown of ZC3H14 Decreases ATP5G1 mRNA LevelsPrevious studies of ZC3H14 orthologs in model organisms suggest a spectrum of post-transcriptional functions (24,25,28) that may influence the fate of bound target transcripts (29). To examine the function of ZC3H14 in human cells, we sought to identify candidate target mRNA transcripts via an unbiased genome-wide approach.…”

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confidence: 99%

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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The long and the short of it: The role of the zinc finger polyadenosine RNA binding protein, Nab2, in control of poly(A) tail length

Cited by 39 publications

References 88 publications

Poly(A) Tail-Mediated Gene Regulation by Opposing Roles of Nab2 and Pab2 Nuclear Poly(A)-Binding Proteins in Pre-mRNA Decay

Poly(A) Tail-Mediated Gene Regulation by Opposing Roles of Nab2 and Pab2 Nuclear Poly(A)-Binding Proteins in Pre-mRNA Decay

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

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