Abstract:Nonsense-mediated mRNA decay (NMD) has originally been described as a surveillance mechanism to inhibit the expression of mRNAs with truncated open reading frames (ORFs) and to contribute to the fidelity of gene expression. It is now recognized that NMD also controls the expression of physiological genes with "intact" mRNA. Stress can decrease NMD efficiency and thus increase the mRNA levels of physiological NMD targets. As stress can also inhibit translation, the net outcome for shaping the proteome is diffic… Show more
“…This study moreover provided evidence that NMD plays a role in the timely termination of the UPR and therewith might protect cells from ER stress‐induced apoptosis . These findings are supported by a very recent paper showing that inhibition of NMD increases protein synthesis of downstream targets of the IRE1 and PERK pathways, suggesting a positive feedback loop in which ER stress dampens NMD, which in turn promotes the ER stress response …”
Nonsense-mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever-rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense.
“…This study moreover provided evidence that NMD plays a role in the timely termination of the UPR and therewith might protect cells from ER stress‐induced apoptosis . These findings are supported by a very recent paper showing that inhibition of NMD increases protein synthesis of downstream targets of the IRE1 and PERK pathways, suggesting a positive feedback loop in which ER stress dampens NMD, which in turn promotes the ER stress response …”
Nonsense-mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever-rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense.
“…He found that NMD suppression did not elicit detectable activation of either the PERK or IRE1α branches of the UPR pathway in U2OS and HeLa cells. Another study conducted in HeLa cells came to the same conclusion [73], as did a study performed in C2C12 myoblast cells [76]. In addition, Karam et al .…”
Section: Nmd and Stress Responses In Mammalsmentioning
confidence: 61%
“…The ability of NMD to target UPR component genes was confirmed recently by a proteomic study conducted by Sieber et al [73]. Through Pulse-SILAC and click-chemistry, these investigators found that several UPR proteins induced by the stressor, Dithiothreitol, were also upregulated in response to UPF1 depletion.…”
Section: Nmd and Stress Responses In Mammalsmentioning
Cells respond to internal and external cellular stressors by activating stress response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly-conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—Nonsense-Mediated RNA Decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.
“…NMD is a surveillance pathway that exists in all eukaryotes [31], [32]. It targets mRNAs harboring PTCs for degradation [33], which if left intact, would lead to production of truncated proteins with predicted deleterious effects for the organism [34]. From a medical view, this suggests that the NMD pathway plays a significant role in modulating the phenotypic outcome of genetic disorders that are caused due to the presence of PTC [35], [36].Fig.…”
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disorder that result as a consequence of a deficiency in the lysosomal hydrolase, a-L-iduronidase enzyme encoded by IDUA gene. Over a hundred causative variants in IDUA have been identified, which result in a progressive multi-systemic disease with a broad range of severity and disease progression reported across affected individuals. The aim of this study was the detection and interpretation of IDUA mutation in a family with two children affected with lethal MPS I. The IDUA gene was sequenced in the parents of two deceased children who had a clinical diagnosis of MPS I, to assess their carrier status and to help inform on risk in future children. The sequencing analysis was performed by PCR and bidirectional Sanger sequencing of the coding region and exon-intron splice junctions at Labor MVZ Westmecklenburg molecular diagnostics laboratory. A heterozygous c.657delA variant in exon 6 was identified in each parent, which is the most likely explanation for disease in their children. This report represents the first Yemeni family to have a molecular diagnosis for MPS I.
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