The meaning of nonsense

Stalder, Lukas; Mühlemann, Oliver

doi:10.1016/j.tcb.2008.04.005

Cited by 144 publications

(138 citation statements)

References 60 publications

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“…A 2-3-fold upregulation of the level of this BRM splice variant in upf1-5 and upf3-1 mutants suggests that the level of this transcript is controlled by the NMD pathway. NMD has been shown not only to degrade aberrant transcripts but also to regulate the steady-state level of many mRNAs involved in numerous cellular processes, such as DNA repair, cell cycle and metabolism (Rehwinkel et al 2005;Stalder and Mühlemann 2008). The answer to the question whether the detected alternative splicing event may be used in the regulation of BRM, for example in response to stress or other signals (Palusa et al 2007) requires further studies.…”

Section: Discussionmentioning

confidence: 99%

“…Premature termination codon-containing transcripts are known to be substrates for degradation via the nonsensemediated decay (NMD) pathway (Stalder and Mühlemann 2008). To determine whether the alternatively spliced BRM mRNA was a target for NMD, we have analysed transcript levels in the Arabidopsis upf1-5 and upf 3-1 Fig.…”

Section: Alternative Splicing Of Brm Transcriptmentioning

confidence: 99%

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Genetic analysis of functional redundancy of BRM ATPase and ATSWI3C subunits of Arabidopsis SWI/SNF chromatin remodelling complexes

Archacki

Sarnowski

Halibart-Puzio

et al. 2009

Planta

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In yeast and mammals, ATP-dependent chromatin remodelling complexes of the SWI/SNF family play critical roles in the regulation of transcription, cell proliferation, diVerentiation and development. Homologues of conserved subunits of SWI/SNF-type complexes, including Snf2-type ATPases and SWI3-type proteins, participate in analogous processes in Arabidopsis. Recent studies indicate a remarkable similarity between phenotypic eVects of mutations in the SWI3 homologue ATSWI3C and bromodomain-ATPase BRM genes. To verify the extent of functional similarity between BRM and ATSWI3C, we have constructed atswi3c brm double mutants and compared their phenotypic traits to those of simultaneously grown single atswi3c and brm mutants. In addition to inheritance of characteristic developmental abnormalities shared by atswi3c and brm mutants, some additive brm-speciWc traits were also observed in the atswi3c brm double mutants. Unlike atswi3c, the brm mutation results in the enhancement of abnormal carpel development and pollen abortion leading to complete male sterility. Despite the overall similarity of brm and atswi3c phenotypes, a critical requirement for BRM in the diVerentiation of reproductive organs suggests that its regulatory functions do not entirely overlap those of ATSWI3C. The detection of two diVerent transcript isoforms indicates that BRM is regulated by alternative splicing that creates an in-frame premature translation stop codon in its SNF2-like ATPase coding domain. The analysis of Arabidopsis mutants in nonsense-mediated decay suggests an involvement of this pathway in the control of alternative BRM transcript level.

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Section: Discussionmentioning

confidence: 99%

Section: Alternative Splicing Of Brm Transcriptmentioning

confidence: 99%

Genetic analysis of functional redundancy of BRM ATPase and ATSWI3C subunits of Arabidopsis SWI/SNF chromatin remodelling complexes

Archacki

Sarnowski

Halibart-Puzio

et al. 2009

Planta

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“…The EJC is a dynamic structure with a heterogeneous protein composition that, among other roles, serves as an anchoring point for UPF2 and UPF3 (Le Hir et al 2001). When an EJC is situated downstream from a TC, the interaction between UPF1 bound to the termination complex and UPF2 and/or UPF3 is greatly facilitated by virtue of their close proximity, resulting in efficient NMD (Nagy and Maquat 1998;Stalder and Muhlemann 2008). A further element potentially resulting in NMD is an open reading frame (ORF) upstream of the main coding sequence.…”

Section: Introductionmentioning

confidence: 99%

Autoregulation of the nonsense-mediated mRNA decay pathway in human cells

Yepiskoposyan¹,

Aeschimann²,

Nilsson³

et al. 2011

RNA

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Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 39-UTR length compared with that of the human mRNAome and were also enriched for 39-UTR introns and uORFs. Intriguingly, most mRNAs coding for NMD factors were among the NMD-sensitive transcripts, implying that the NMD process is autoregulated. These mRNAs all possess long 39 UTRs, and some of them harbor uORFs. Using reporter gene assays, we demonstrated that the long 39 UTRs of UPF1, SMG5, and SMG7 mRNAs are the main NMD-inducing features of these mRNAs, suggesting that long 39 UTRs might be a frequent trigger of NMD.

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“…Moreover, it is sometimes difficult to detect the mRNA affected by a truncating mutation because of the activation of the nonsense-mediated mRNA decay pathway. 3 Functional assays of the effect of VUS on RNA splicing, using patient genomic DNA and a splicing reporter hybrid minigene, …”

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confidence: 99%

Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

et al. 2011

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A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A4G and BRCA1 c.5194À12G4A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977À7C4G induced in frame inclusion of 6 nt from the 3¢ end of intron 17. The novel variants BRCA2 c.520C4T and BRCA2 c.7992T4A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions. Keywords: variants of unknown significance; splicing defects; splicing reporter minigene; breast and ovarian cancer; BRCA1 and BRCA2 INTRODUCTIONThe interpretation of variants of unknown significance (VUS) found in the molecular screenings of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, is essential for genetic counseling of patients and their families and for the implementation of new therapies targeted to carriers of BRCA mutations, such as those based on poly-(ADP-ribose) polymerase inhibitors. 1 The number of these variants already exceeds that of the reported pathogenic mutations, and is expected to increase rapidly with the use of new high throughput sequencing technologies that are based on massive parallel sequencing. 2 It is now widely accepted that RNA analyses should be used to improve the assessment of pathogenicity of sequence variation, because a large fraction of sequence variants, both intronic and exonic, may induce splicing defects. However, in many cases, patient RNA is either not available or it has been obtained in ways that do not ensure its stability. Moreover, it is sometimes difficult to detect the mRNA affected by a truncating mutation because of the activation of the nonsense-mediated mRNA decay pathway. 3 Functional assays of the effect of VUS on RNA splicing, using patient genomic DNA and a splicing reporter hybrid minigene,

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The meaning of nonsense

Cited by 144 publications

References 60 publications

Genetic analysis of functional redundancy of BRM ATPase and ATSWI3C subunits of Arabidopsis SWI/SNF chromatin remodelling complexes

Genetic analysis of functional redundancy of BRM ATPase and ATSWI3C subunits of Arabidopsis SWI/SNF chromatin remodelling complexes

Autoregulation of the nonsense-mediated mRNA decay pathway in human cells

Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

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