The abundance of RNPS1, a protein component of the exon junction complex, can determine the variability in efficiency of the Nonsense Mediated Decay pathway

Viegas, Marcelo; Gehring, Niels H.; Breit, Stephen; Hentze, Matthias W.; Kulozik, Andreas E.

doi:10.1093/nar/gkm461

Cited by 111 publications

(128 citation statements)

References 42 publications

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“…The mRNA levels of three different natural NMD substrates (SC35, NAT9 and TBL2) [11][12][13] were measured in cells incubated with staurosporine or DMSO. The mRNA levels of these substrates were compared to the level of three reference mRNAs that are not subject to NMD (GAPDH, Actin or RPL32).…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10] In addition to its role in quality control, NMD also regulates gene expression of so-called natural substrates of NMD. [11][12][13][14][15] Proteins that have a central role in NMD, such as UPF1, UPF2, UPF3/UPF3a and UPF3X/UPF3b are highly conserved from yeast to human. The requirement for these UPF proteins in NMD is illustrated by the fact that the downregulation of any one of them results in an inhibition of NMD.…”

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confidence: 99%

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Caspases shutdown nonsense-mediated mRNA decay during apoptosis

et al. 2015

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Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that plays integral roles in eliminating mRNAs with premature termination codons to prevent the synthesis of truncated proteins that could be pathogenic. One response to the accumulation of detrimental proteins is apoptosis, which involves the activation of enzymatic pathways leading to protein and nucleic acid cleavage and culminating in cell death. It is not clear whether NMD is required to ensure the accurate expression of apoptosis genes or is no longer necessary since cytotoxic proteins are not an issue during cell death. The present study shows that caspases cleave the two NMD factors UPF1 and UPF2 during apoptosis impairing NMD. Our results demonstrate a new regulatory pathway for NMD that occurs during apoptosis and provide evidence for role of the UPF cleaved fragments in apoptosis and NMD inhibition.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Caspases shutdown nonsense-mediated mRNA decay during apoptosis

et al. 2015

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“…Recently, NMD efficiency has been shown to vary between cell types, tissues and individuals with the growing idea that the NMD pathway could act as a modulator of genetic disease severity. 16 The mechanisms by which mutations in the COL3A1 gene produce diseases are still poorly understood. So far, all the mutations reported in COL3A1 have been linked to an autosomal dominant pathway of inheritance.…”

Section: Discussionmentioning

confidence: 99%

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

et al. 2009

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So far, mutations in the human COL3A1 gene have been associated with the predominantly inherited Ehlers-Danlos syndrome (EDS), vascular type. Genotype -phenotype correlation perspectives collapsed, as haploinsufficiency, which was long suggested to confer a milder or unrecognized phenotype, was reported in four patients with a phenotype similar to that of vascular EDS. Here, we study a case of recessive EDS in a young consanguineous girl of healthy parents. She fulfilled the vascular EDS criteria for laboratory testing. Total sequencing of COL3A1 cDNA identified a homozygous nucleotide duplication (c.479dupT) resulting in a premature termination codon (p.Lys161GlnfsX45). Studies in genomic DNA showed that this mutation was inherited from each parent. The expression analysis (RT-PCR, quantitative-PCR, immunohistochemistry, WB) showed strong mRNA decay and an absence of type III collagen in the proband. The expected COL3A1 haploinsufficiency in her healthy ascendants did not lead to the manifestations of vascular EDS. This case provides evidence of a stochastic effect of COL3A1 haploinsufficiency in humans, which could be explained by the relation between nonsense-mediated mRNA decay efficiency and the resulting dominant-negative effect depending on the position of the mutation and/or modifying factors. It opens up new perspectives for the understanding of COL3A1 genotype -phenotype correlations, which is required while considering targeted therapy.

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“…The relative quantities of the CDA and BLM cDNAs were normalized against four reference genes (RPL32, HPRT1, HMBS and SDHA) chosen on the basis of their low M-value 28 . The primer sequences for BLM, RPL32, HPRT1, HMBS and SDHA have been described in previous publications [28][29][30] . CDA primer sequences: primer 1 (5′-CCCTACAGTCACTTTCCTG-3′) and primer 2 (5′-CGGGTAGCAGG CATTTTCTA-3′).…”

Section: Methodsmentioning

confidence: 99%