Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis

Apponi, Luciano H.; Leung, Sara W.; Williams, Kathryn R.; Valentini, Sandro Roberto; Corbett, Anita H.; Pavlath, Grace K.

doi:10.1093/hmg/ddp569

Cited by 108 publications

(143 citation statements)

References 44 publications

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“…This study also shows drastic accumulation of polyadenylated RNA in the nucleus of PABPN1-depleted cells, suggesting a role for PABPN1 in mRNA export. 41 Interestingly, this robust mRNA export defect was not accompanied by mRNA hyperadenylation, a phenotype that was previously associated with mRNA export defects in yeast, fruit flies and mammalian cells. 7,29,42,43 In Drosophila, specific pabp2 mutants also show shorter poly(A) tails using total RNA or individual mRNAs.…”

Section: Resultsmentioning

confidence: 65%

“…40 Although these aforementioned evidence are mostly indirect, more recent gene silencing experiments using primary mouse cells support the role of PABPN1 as a general mRNA polyadenylation factor. 41 The fact that the hypoadenylation phenotype of PABPN1-depleted cells did not significantly alter the expression levels of poly(A) + RNAs is intriguing, however, given the important role of the 3' poly(A) tail in mRNA expression. This study also shows drastic accumulation of polyadenylated RNA in the nucleus of PABPN1-depleted cells, suggesting a role for PABPN1 in mRNA export.…”

Section: Resultsmentioning

confidence: 99%

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Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

Lemay

Lemieux²,

St-André³

et al. 2010

RNA Biology

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T he addition of a 3' poly(A) tail is a pre-requisite for the maturation of the majority of eukaryotic transcripts. In most eukaryotic species, RNA poly(A) tails are bound by two important poly(A)-binding proteins (PABPs): PABPC1 and PABPN1 that localize to the cytoplasm and the nucleus, respectively. Such steady state localization for PABPN1 and PABPC1 led to a model whereby PABPN1-bound nuclear mRNAs are remodeled during or after nuclear export so that PABPN1 is replaced by PABPC1 to allow robust cap-dependent translation in the cytoplasm. Here we discuss evidence that challenge the view in which PABPN1 and PABPC1 function solely in the nucleus and cytoplasm, respectively. We discuss accumulating evidence that support nuclear roles for PABPC1 in mRNA biogenesis as well as cytoplasmic roles for PABPN1 in translational control. Because 3' poly(A) tails can also act as a degradation mark via the exosome complex of 3'-5' exonucleases, we also discuss recent results that involve the nuclear PABP in posttranscriptional gene regulation.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

Lemay

Lemieux²,

St-André³

et al. 2010

RNA Biology

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“…34,35 Briefly, mice were sacrificed and TA, gastrocnemius, and extensor digitorum longus muscles were isolated. Excess connective tissues and fat were cleaned in sterile PBS followed by mincing of skeletal muscle in Dulbecco's Modified Eagle's Medium and enzymatic dissociation with 0.1% pronase.…”

Section: Primary Myoblast Isolation and Fusion Assaysmentioning

confidence: 99%

Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

Mittal

Bhatnagar

Kumar

et al. 2010

The American Journal of Pathology

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Impairment in the regeneration process is a critical determinant for skeletal muscle wasting in chronic diseases and degenerative muscle disorders. Inflammatory cytokines are known to cause significant muscle wasting , however, their role in myofiber regeneration is less clear. In this study we have investigated the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in skeletal muscle regeneration in vivo. Our results show that expression levels of TWEAK and its receptor Fn14 are significantly increased in skeletal muscles of mice after injury. Genetic deletion of TWEAK increased the fiber crosssectional area and levels of embryonic isoform of myosin heavy chain in regenerating tibial anterior muscle. Conversely , muscle-specific transgenic overexpression of TWEAK reduced the fiber cross-sectional area and levels of the embryonic myosin heavy chain in regenerating muscle. TWEAK induced the expression of several inflammatory molecules and increased interstitial fibrosis in regenerating muscle. Genetic ablation of TWEAK suppressed, whereas overexpression of TWEAK increased, the activation of nuclear factor-kappa B without affecting the activation of Akt or p38 kinase in regenerating myofibers. Primary myoblasts from TWEAK-null mice showed enhanced differentiation in vitro, whereas myoblasts from TWEAK-Tg mice showed reduced differentiation compared with wild-type mice. Collectively, our study suggests that TWEAK negatively regulates muscle regeneration and that TWEAK is a potential therapeutic target to enhance skeletal muscle regeneration in vivo. (Am J

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“…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).…”

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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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Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis

Cited by 108 publications

References 44 publications

Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

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

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