Splice variants of the human ZC3H14 gene generate multiple isoforms of a zinc finger polyadenosine RNA binding protein

Leung, Sara W.; Apponi, Luciano H.; Cornejo, Omar E.; Kitchen, Chad M.; Valentini, Sandro Roberto; Pavlath, Grace K.; Dunham, C.M.; Corbett, Anita H.

doi:10.1016/j.gene.2009.02.022

Cited by 47 publications

(113 citation statements)

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“…Tpr-regulated mRNA export www.rnajournal.org 1351 human/mouse poly(A)-binding proteins expressed from the gene ZC3H14 may serve in this function (Leung et al 2009). Also, several previous studies suggest a coupling between the polyadenylation machinery and mRNA export in mammalian cells (for review, see Zhao et al 1999).…”

Section: Discussionmentioning

confidence: 99%

The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway

Coyle¹,

Bor²,

Rekosh³

et al. 2011

RNA

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Post-transcriptional regulation of mRNA includes restriction mechanisms to prevent export and expression of mRNAs that are incompletely spliced. Here we present evidence that the mammalian protein Tpr is involved in this restriction. To study the role of Tpr in export of mRNA with retained introns, we used reporters in which the mRNA was exported either via the Nxf1/Nxt1 pathway using a CTE or via the Crm1 pathway using Rev/RRE. Our data show that even modest knockdown of Tpr using RNAi leads to a significant increase in export and translation from the mRNA containing the CTE. In contrast, Tpr perturbation has no effect on export of mRNA containing the RRE, either in the absence or presence of Rev. Also, no effects were observed on export of a completely spliced mRNA. Taken together, our results indicate that Tpr plays an important role in quality control of mRNA trafficked on the Nxf1 pathway.

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Section: Discussionmentioning

confidence: 99%

The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway

Coyle¹,

Bor²,

Rekosh³

et al. 2011

RNA

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“…Recently, mutations in the human ZC3H14 gene, which encodes a zinc finger polyadenosine RNA-binding protein (Leung et al 2009), were linked to inherited, nonsyndromic, intellectual disability revealing the critical role of this Pab protein in the brain (Pak et al 2011;Kelly et al 2012). The ZC3H14 protein (also termed mSUT-2) (Guthrie et al 2009(Guthrie et al , 2011, belongs to an evolutionarily conserved, ubiquitously expressed family of Cys 3 His tandem zinc-finger (ZnF) polyadenosine (poly(A)) RNA-binding proteins (Anderson et al 1993;Hector et al 2002;Kelly et al 2007;Leung et al 2009;Pak et al 2011). The mammalian ZC3H14 locus encodes three long protein isoforms (isoforms 1-3) that at steady state localize to the nucleus and one short isoform (isoform 4) that localizes to the cytoplasm (Leung et al 2009;Kelly et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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

Kelly

Leung

Pak

et al. 2014

RNA

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The ZC3H14 gene, which encodes a ubiquitously expressed, evolutionarily conserved, nuclear, zinc finger polyadenosine RNAbinding protein, was recently linked to autosomal recessive, nonsyndromic intellectual disability. Although studies have been carried out to examine the function of putative orthologs of ZC3H14 in Saccharomyces cerevisiae, where the protein is termed Nab2, and Drosophila, where the protein has been designated dNab2, little is known about the function of mammalian ZC3H14. Work from both budding yeast and flies implicates Nab2/dNab2 in poly(A) tail length control, while a role in poly(A) RNA export from the nucleus has been reported only for budding yeast. Here we provide the first functional characterization of ZC3H14. Analysis of ZC3H14 function in a neuronal cell line as well as in vivo complementation studies in a Drosophila model identify a role for ZC3H14 in proper control of poly(A) tail length in neuronal cells. Furthermore, we show here that human ZC3H14 can functionally substitute for dNab2 in fly neurons and can rescue defects in development and locomotion that are present in dNab2 null flies. These rescue experiments provide evidence that this zinc finger-containing class of nuclear polyadenosine RNA-binding proteins plays an evolutionarily conserved role in controlling the length of the poly(A) tail in neurons.

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“…The ZC3H14 gene encodes an evolutionarily conserved Cys 3 His (CCCH) tandem ZnF polyadenosine RNA binding protein 2 ( Fig. 1).…”

Section: Members Of a Family Of Znf-containing Pabs Perform Conservedmentioning

confidence: 99%

“…Importantly, all four forms of the ZC3H14 protein share the same array of consecutive ZnFs in the C-terminal RNA binding domain, suggesting that they all bind polyadenosine RNA. At steady-state, ZC3H14 isoforms 1-3 localize primarily to the nucleus and are enriched in SC35-positive nuclear speckles, 2 which are sites of RNA metabolism. 10 In mouse brain sections, ZC3H14 isoforms 1-3 colocalize with bulk poly(A) RNA in the cell bodies of hippocampal neurons.…”

Section: Members Of a Family Of Znf-containing Pabs Perform Conservedmentioning

confidence: 99%

“…1 In contrast, ZC3H14 isoform 4 protein localizes to the cytoplasm at steady-state and shows tissue-specific expression with enrichment in the brain and testes. 2 Given the differential localization of these isoforms and the variability in tissue expression of isoform 4, these nuclear and cytoplasmic isoforms of the vertebrate ZC3H14 protein may play tissue-specific roles in modulating gene expression.…”

Section: Members Of a Family Of Znf-containing Pabs Perform Conservedmentioning

confidence: 99%

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Kelly¹,

Pak²,

Garshasbi³

et al. 2012

RNA Biology

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Polyadenosine RNA binding proteins (Pabs) play critical roles in regulating the polyadenylation, nuclear export, stability and translation of cellular RNAs. Although most Pabs are ubiquitously expressed and are thought to play general roles in post-transcriptional regulation, mutations in genes encoding these factors have been linked to tissue-specific diseases including muscular dystrophy and now intellectual disability (ID). Our recent work defined this connection to ID, as we showed that mutations in the gene encoding the ubiquitously expressed Cys 3 His tandem zinc-finger (ZnF) Pab, ZC3H14 (Zinc finger protein, CCCH-type, number 14) are associated with non-syndromic autosomal recessive intellectual disability (NS-ARID). This study provided a first link between defects in Pab function and a brain disorder, suggesting that ZC3H14 plays a required role in regulating RNAs in nervous system cells. Here we highlight key questions raised by our study of ZC3H14 and its ortholog in the fruit fly Drosophila melanogaster, dNab2 and comment on future approaches that could provide insights into the cellular and molecular roles of this class of zinc fingercontaining Pabs. We propose a summary model depicting how ZC3H14-type Pabs might play particularly important roles in neuronal RNA metabolism.

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Splice variants of the human ZC3H14 gene generate multiple isoforms of a zinc finger polyadenosine RNA binding protein

Cited by 47 publications

References 50 publications

The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway

The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway

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

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