Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay

Zhang, Zhenguo; Xin, Dedong; Wang, Ping; Zhou, Li; Hu, Landian; Kong, Xiangyin; Hurst, Laurence D.

doi:10.1186/1741-7007-7-23

Cited by 70 publications

(68 citation statements)

References 76 publications

(132 reference statements)

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“…While it is difficult to quantitatively assess the expression of such proteins, multiple studies have demonstrated that alternatively spliced mRNAs accumulate with NMD inhibition (6)(7)(8)10). Although the physiological/pathological inhibition of NMD occurs with eIF2␣ is phosphorylation, a condition that blunts translation, we have demonstrated that many mRNAs stabilized with NMD inhibition are still actively translated despite eIF2␣ phosphorylation, including functional proteins and maladaptive peptides (3,5).…”

Section: Discussionmentioning

confidence: 88%

“…However, the full biological consequences of NMD regulation are unknown. These consequences include the stabilization of mutated and alternatively spliced transcripts which could encode deleterious dominant negative, truncated, and/or misfolded proteins (6)(7)(8)(9)(10). The recognition that NMD is dynamically regulated raises the question of how the cell adapts to these aberrant proteins when NMD is physiologically or pathologically inhibited.…”

mentioning

confidence: 99%

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Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy

Wengrod

Martin

Wang

et al. 2013

Molecular and Cellular Biology

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Nonsense-mediated RNA decay (NMD) is an mRNA surveillance mechanism which rapidly degrades select cytoplasmic mRNAs. We and others have shown that NMD is a dynamically regulated process inhibited by amino acid deprivation, hypoxia, and other cellular stresses commonly generated by the tumor microenvironment. This inhibition of NMD can result in the accumulation of misfolded, mutated, and aggregated proteins, but how cells adapt to these aberrant proteins is unknown. Here we demonstrate that the inhibition of NMD activates autophagy, an established protein surveillance mechanism, both in vitro and in vivo. Conversely, the hyperactivation of NMD blunts the induction of autophagy in response to a variety of cellular stresses. The regulation of autophagy by NMD is due, in part, to stabilization of the documented NMD target ATF4. NMD inhibition increases intracellular amino acids, a hallmark of autophagy, and the concomitant inhibition of autophagy and NMD, either molecularly or pharmacologically, leads to synergistic cell death. Together these studies indicate that autophagy is an adaptive response to NMD inhibition and uncover a novel relationship between an mRNA surveillance system and a protein surveillance system, with important implications for the treatment of cancer. N onsense-mediated RNA decay (NMD) is a cellular surveillance system that rapidly degrades select mRNAs. While the exact mechanism of NMD is still not completely delineated, current models suggest that during a pioneer round of translation, the translation complex pauses at premature termination codons (PTCs) upstream of exon junction complexes (EJCs). Crucial components of the NMD mechanism, including Upf1/Rent1 and Upf2/Rent2, bridge the EJC to a paused translation complex and initiate RNA degradation. In addition to PTCs located upstream of EJCs, long 3= untranslated regions and other, less-well-defined features of the processed mRNA transcript can result in mRNA degradation by NMD (reviewed in reference 1). Up to 30% of all mutations responsible for human genetic disorders, including cystic fibrosis, muscular dystrophy, and thalassemia, result in PTCs upstream of EJCs (2). NMD also degrades nonmutated mRNAs, including those important for the response to cellular stress and amino acid transport (3-5). The recent observation that NMD is inhibited by amino acid deprivation, hypoxia, the accumulation of unfolded proteins in the endoplasmic reticulum (ER), and other cellular stresses that lead to the phosphorylation of eukaryotic initiation factor 2␣ (eIF2␣) has led to a greater appreciation of the potential role that the dynamic regulation of gene expression by NMD could play in physiology and pathology (3-5).The stress-induced inhibition of NMD stabilizes the stressresponsive transcription factor ATF4, augments the ER stress response, and permits cells to grow in soft agar and as tumor explants, conditions in which cells are deprived of nutrients and oxygen (5). However, the full biological consequences of NMD regulation are unknown. These conse...

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy

Wengrod

Martin

Wang

et al. 2013

Molecular and Cellular Biology

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“…Thus, the regulation of unproductive splicing of SR protein transcripts is proposed to play a role in the auto-regulation or homeostatic control of these splicing regulators. 18 Consistent with this, Zhang et al 13 examined human and mouse orthologues of well annotated protein coding genes for PTC containing transcript isoforms and determined that only the small fraction (2%) that exhibited strong evolutionary conservation of the PTC containing transcript isoforms were likely to represent bona fide examples of regulated unproductive splicing coupled to NMD. These observations suggest that the portions of the gene directly influencing production of the PTC containing isoform are under purifying selection and will remain conserved between organisms with conserved PTC containing splice isoforms, assuming that the mechanisms of alternative splice determination and PTC recognition were also conserved.…”

Section: W Brad Barbazukmentioning

confidence: 81%

“…13 While many PTC containing transcript isoforms may result from imprecise splicing, there remain several examples of genes that are truly regulated by coupling PTC containing alternatively spliced transcript isoforms with NMD. The majority of these encode components of the ribosome 14,15 and splicing machinery.…”

Section: W Brad Barbazukmentioning

confidence: 99%

A conserved alternative splicing event in plants reveals an ancient exonization of 5S rRNA that regulates TFIIIA

Barbazuk

2010

RNA Biology

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“…Nonsense mediated decay (NMD) is a molecular surveillance mechanism that selectively degrades aberrant transcripts produced as a result of nonsense or splice-site variants [234][235][236]. NMD of aberrant transcripts should result in extreme allelic ratios (close to zero or one).…”

Section: Majority Of Aberrant Alleles Do Not Affect Expression Severelymentioning

confidence: 99%

Functional Analysis of Genomic Variation and Impact on Molecular and Higher Order Phenotypes

Pandey¹

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Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay

Cited by 70 publications

References 76 publications

Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy

Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy

A conserved alternative splicing event in plants reveals an ancient exonization of 5S rRNA that regulates TFIIIA

Functional Analysis of Genomic Variation and Impact on Molecular and Higher Order Phenotypes

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