Nuclear retention of mRNAs – quality control, gene regulation and human disease

Wegener, Marius; Müller-McNicoll, Michaela

doi:10.1016/j.semcdb.2017.11.001

Cited by 63 publications

(82 citation statements)

References 140 publications

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“…By abolishing their expressions individually via specific siRNAs, our results were consistent with the scenario that p54 nrb effects a nucleus-biased distribution of LIMD1 mRNA ( Fig EV5D). Incidentally, this factor has been reported to cooperate with ADAR1 in nuclear sequestration of transcripts [37]. Our results in this part then served as additional evidence for the contribution of ADAR1mediated spatial control in the expression of LIMD1 transcript.…”

Section: Adar1 Regulates Limd1 Mrna Subcellular Distribution and Conssupporting

confidence: 71%

ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF‐1α‐inhibiting factors

Liu

Chang

et al. 2019

EMBO Reports

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Adenosine deaminase acting on RNA (ADAR)‐catalyzed adenosine‐to‐inosine RNA editing is potentially dysregulated in neoplastic progression. However, how this transcriptome recoding process is functionally correlated with tumorigenesis remains largely elusive. Our analyses of RNA editome datasets identify hypoxia‐related genes as A‐to‐I editing targets. In particular, two negative regulators of HIF‐1A—the natural antisense transcript HIF1A‐AS2 and the ubiquitin ligase scaffold LIMD1—are directly but differentially modulated by ADAR1. We show that HIF1A‐AS2 antagonizes the expression of HIF‐1A in the immediate‐early phase of hypoxic challenge, likely through a convergent transcription competition in cis. ADAR1 in turn suppresses transcriptional progression of the antisense gene. In contrast, ADAR1 affects LIMD1 expression post‐transcriptionally, by interfering with the cytoplasmic translocation of LIMD1 mRNA and thus protein translation. This multi‐tier regulation coordinated by ADAR1 promotes robust and timely accumulation of HIF‐1α upon oxygen depletion and reinforces target gene induction and downstream angiogenesis. Our results pinpoint ADAR1‐HIF‐1α axis as a hitherto unrecognized key regulator in hypoxia.

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Section: Adar1 Regulates Limd1 Mrna Subcellular Distribution and Conssupporting

confidence: 71%

ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF‐1α‐inhibiting factors

Liu

Chang

et al. 2019

EMBO Reports

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“…The ability of retained introns described as 'detained' introns to evade NMD has previously been reported (Boutz et al, 2015). Detained introns are a special class of introns that are poorly spliced and retained in the nucleus in order to modulate gene expression (Fu, 2017;Wegener and Müller-McNicoll, 2017). Interestingly, CLK1 itself has been shown to regulate the alternative splicing of nuclear 'detained' introns in hundreds of other genes (Boutz, Bhutkar & Sharp, 2015).…”

Section: Discussionmentioning

confidence: 91%

Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention

Uzor

Zorzou

Bowler

et al. 2018

Gene

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Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the CLK1, CLK2, CLK3 and CLK4 genes. The expression of CLK1 is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLK (arising from exon 4 skipping) and CLK (arising from intron 4 retention). We examined CLK1 alternative splicing in a range of cancer cell lines, and report widespread and highly variable rates of exon 4 skipping and intron 4 retention. We also examined the effect of severe environmental stress including heat shock, osmotic shock, and exposure to the alkaloid drug harmine on CLK1 alternative splicing in DU145 prostate cancer cells. All treatments rapidly reduced exon 4 skipping and intron 4 retention, shifting the balance towards full-length CLK1 expression. We also found that the inhibition of CLK1 with the benzothiazole TG003 reduced exon 4 skipping and intron 4 retention suggesting an autoregulatory mechanism. CLK1 inhibition with TG003 also resulted in modified alternative splicing of five cancer-associated genes.

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“…Incompletely spliced mRNAs are retained within nuclear speckles (NS) in mammalian cells [17]. NS are membraneless nuclear domains enriched in mRNA splicing factors, 3 processing factors, and export factors, and they are located in the interchromatin regions of the nucleoplasm.…”

Section: Relationship Between Alternative Splicing and Nmd And Mrna Lmentioning

confidence: 99%

“…Early spliceosomal components, U1 snRNP and U2AF2 and SR proteins, are reported to be associated with nuclear retention [17]. In one study, depletion of U1 snRNP protein component, U1-70K, and U2AF2 prevented nuclear retention of unspliced human β-globin reporter transcripts and caused their leakage into the cytoplasm [48].…”

Section: Relationship Between Alternative Splicing and Nmd And Mrna Lmentioning

confidence: 99%

“…The TREX complex is recruited to mRNA in a splicing-dependent manner via splicing factor and UAP56, and it triggers the association of nuclear RNA export factor 1 (NXF1), which is a final mRNA export factor, onto the export competent mRNA. Recently, a molecular mechanism that suppresses the recruitment of NXF1 to incompletely spliced mRNAs was partly demonstrated [15][16][17]. In addition, gene regulation through nonsense-mediated mRNA decay (NMD) was shown [18][19][20][21][22][23][24].The aberrant transcript with the pre-mature termination codon, derived from abnormal splicing, is removed by NMD.…”

Section: Introductionmentioning

confidence: 99%

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Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

Fujita

Ishizuka

Mitsukawa

et al. 2020

IJMS

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Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential.

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Nuclear retention of mRNAs – quality control, gene regulation and human disease

Cited by 63 publications

References 140 publications

ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF‐1α‐inhibiting factors

ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF‐1α‐inhibiting factors

Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

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