scholarly journals Regulated Intron Retention and Nuclear Pre-mRNA Decay Contribute toPABPN1Autoregulation

2015 ◽  
Vol 35 (14) ◽  
pp. 2503-2517 ◽  
Author(s):  
Danny Bergeron ◽  
Gheorghe Pal ◽  
Yves B. Beaulieu ◽  
Benoit Chabot ◽  
François Bachand
Keyword(s):  
Molecular Basis ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Late Onset ◽  
Intron Retention ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Rich Region ◽  
Functional Roles ◽  
Nuclear Exosome ◽  
Nuclear Transcript

The poly(A)-binding protein nuclear 1 is encoded by thePABPN1gene, whose mutations result in oculopharyngeal muscular dystrophy, a late-onset disorder for which the molecular basis remains unknown. Despite recent studies investigating the functional roles of PABPN1, little is known about its regulation. Here, we show that PABPN1 negatively controls its own expression to maintain homeostatic levels in human cells. Transcription from thePABPN1gene results in the accumulation of two major isoforms: an unspliced nuclear transcript that retains the 3′-terminal intron and a fully spliced cytoplasmic mRNA. Increased dosage of PABPN1 protein causes a significant decrease in the spliced/unspliced ratio, reducing the levels of endogenous PABPN1 protein. We also show that PABPN1 autoregulation requires inefficient splicing of its 3′-terminal intron. Our data suggest that autoregulation occurs via the binding of PABPN1 to an adenosine (A)-rich region in its 3′ untranslated region, which promotes retention of the 3′-terminal intron and clearance of intron-retained pre-mRNAs by the nuclear exosome. Our findings unveil a mechanism of regulated intron retention coupled to nuclear pre-mRNA decay that functions in the homeostatic control of PABPN1 expression.

scholarly journals A Yeast Homologue of Hsp70, Ssa1p, Regulates Turnover of the MFA2 Transcript through Its AU-Rich 3′ Untranslated Region

2003 ◽  
Vol 23 (8) ◽  
pp. 2623-2632 ◽  
Author(s):  
Radharani Duttagupta ◽  
Shobha Vasudevan ◽  
Carol J. Wilusz ◽  
Stuart W. Peltz
Keyword(s):  
Untranslated Region ◽  
Mrna Decay ◽  
Critical Role ◽  
Temperature Sensitive ◽  
Rich Region ◽  
Rapid Decay ◽  
Chaperone Protein ◽  
Eukaryotic Mrnas ◽  
Necessary And Sufficient ◽  
Dependent Mechanism

ABSTRACT Many eukaryotic mRNAs exhibit regulated decay in response to cellular signals. AU-rich elements (AREs) identified in the 3′ untranslated region (3′-UTR) of several such mRNAs play a critical role in controlling the half-lives of these transcripts. The yeast ARE-containing mRNA, MFA2, has been studied extensively and is degraded by a deadenylation-dependent mechanism. However, the trans-acting factors that promote the rapid decay of MFA2 have not been identified. Our results suggest that the chaperone protein Hsp70, encoded by the SSA family of genes, is involved in modulating MFA2 mRNA decay. MFA2 is specifically stabilized in a strain bearing a temperature-sensitive mutation in the SSA1 gene. Furthermore, an AU-rich region within the 3′-UTR of the message is both necessary and sufficient to confer this regulation. Stabilization occurs as a result of slower deadenylation in the ssa1ts strain, suggesting that Hsp70 is required for activation of the turnover pathway.

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

scholarly journals Rrp47p Is an Exosome-Associated Protein Required for the 3′ Processing of Stable RNAs

2003 ◽  
Vol 23 (19) ◽  
pp. 6982-6992 ◽  
Author(s):  
Philip Mitchell ◽  
Elisabeth Petfalski ◽  
Rym Houalla ◽  
Alexandre Podtelejnikov ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Nuclear Protein ◽  
Rrna Processing ◽  
Small Nucleolar Rna ◽  
Whole Cell ◽  
Cell Lysates ◽  
Small Nuclear Rnas ◽  
Nuclear Exosome ◽  
Nucleolar Rna

ABSTRACT Related exosome complexes of 3′→5′ exonucleases are present in the nucleus and the cytoplasm. Purification of exosome complexes from whole-cell lysates identified a Mg2+-labile factor present in substoichiometric amounts. This protein was identified as the nuclear protein Yhr081p, the homologue of human C1D, which we have designated Rrp47p (for rRNA processing). Immunoprecipitation of epitope-tagged Rrp47p confirmed its interaction with the exosome and revealed its association with Rrp6p, a 3′→5′ exonuclease specific to the nuclear exosome fraction. Northern analyses demonstrated that Rrp47p is required for the exosome-dependent processing of rRNA and small nucleolar RNA (snoRNA) precursors. Rrp47p also participates in the 3′ processing of U4 and U5 small nuclear RNAs (snRNAs). The defects in the processing of stable RNAs seen in rrp47-Δ strains closely resemble those of strains lacking Rrp6p. In contrast, Rrp47p is not required for the Rrp6p-dependent degradation of 3′-extended nuclear pre-mRNAs or the cytoplasmic 3′→5′ mRNA decay pathway. We propose that Rrp47p functions as a substrate-specific nuclear cofactor for exosome activity in the processing of stable RNAs.

scholarly journals The 5′-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress

FEBS Journal ◽  
2013 ◽  
Vol 280 (18) ◽  
pp. 4693-4707 ◽  
Author(s):  
Masaya Hatano ◽  
Mariko Umemura ◽  
Natsumi Kimura ◽  
Takashi Yamazaki ◽  
Hitoshi Takeda ◽  
...  
Keyword(s):  
Environmental Stress ◽  
Mrna Stability ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Nonsense Mediated Mrna Decay

scholarly journals HuR Uses AUF1 as a Cofactor To Promote p16INK4 mRNA Decay

2010 ◽  
Vol 30 (15) ◽  
pp. 3875-3886 ◽  
Author(s):  
Na Chang ◽  
Jie Yi ◽  
Gaier Guo ◽  
Xinwen Liu ◽  
Yongfeng Shang ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Loop Structure ◽  
Wild Type ◽  
Stem Loop ◽  
Human Diploid Fibroblasts ◽  
Stem Loop Structure ◽  
Chimeric Transcripts ◽  
P16 Expression

ABSTRACT In this study, we show that HuR destabilizes p16INK4 mRNA. Although the knockdown of HuR or AUF1 increased p16 expression, concomitant AUF1 and HuR knockdown had a much weaker effect. The knockdown of Ago2, a component of the RNA-induced silencing complex (RISC), stabilized p16 mRNA. The knockdown of HuR diminished the association of the p16 3′ untranslated region (3′UTR) with AUF1 and vice versa. While the knockdown of HuR or AUF1 reduced the association of Ago2 with the p16 3′UTR, Ago2 knockdown had no influence on HuR or AUF1 binding to the p16 3′UTR. The use of EGFP-p16 chimeric reporter transcripts revealed that p16 mRNA decay depended on a stem-loop structure present in the p16 3′UTR, as HuR and AUF1 destabilized EGFP-derived chimeric transcripts bearing wild-type sequences but not transcripts with mutations in the stem-loop structure. In senescent and HuR-silenced IDH4 human diploid fibroblasts, the EGFP-p16 3′UTR transcript was more stable. Our results suggest that HuR destabilizes p16 mRNA by recruiting the RISC, an effect that depends on the secondary structure of the p16 3′UTR and requires AUF1 as a cofactor.

scholarly journals Reactive Oxygen Species Regulate Ceruloplasmin by a Novel mRNA Decay Mechanism Involving Its 3′-Untranslated Region

2008 ◽  
Vol 284 (3) ◽  
pp. 1873-1883 ◽  
Author(s):  
Nisha Tapryal ◽  
Chaitali Mukhopadhyay ◽  
Dola Das ◽  
Paul L. Fox ◽  
Chinmay K. Mukhopadhyay
Keyword(s):  
Reactive Oxygen Species ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Decay Mechanism
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