RNA surveillance: unforeseen consequences for gene expression, inherited genetic disorders and cancer

Culbertson, Michael R.

doi:10.1016/s0168-9525(98)01658-8

Cited by 361 publications

(259 citation statements)

References 51 publications

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“…In aberrant splicing, portions of exons, portions of introns or both are retained within transcripts that fail to be purged by the cellular pathways designed to scavenge abnormal mRNAs, such as nonsense-mediated decay (Culbertson, 1999;Wilkinson and Shyu, 2002). Often, the aberrant mRNAs produce truncated proteins that in some cases allow them to function in a dominantnegative manner.…”

Section: Discussionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5 0 end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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“…It is possible that a single functional carboxy-terminus is sufficient to activate transcription but alternatively the MESP1 protein may compensate for the absence of MESP2 function, just as MesP1 can rescue the axial skeletal defects in MesP2-deficient mice in a dosage-dependent manner (Saga, 1998). Another possibility is that the mutant MESP2 transcript, containing a premature stop codon at 1099 -1101 bp, is degraded by nonsense-mediated RNA decay, with no truncated protein being produced (Culbertson, 1999).…”

Section: Mesoderm Posterior 2 (Mesp2)mentioning

confidence: 99%

Abnormal vertebral segmentation and the notch signaling pathway in man

Turnpenny

Alman

Cornier

et al. 2007

Developmental Dynamics

145

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Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.

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“…This is especially important in the comparison of constructs harboring nonsense mutations, since transcripts containing a premature stop codon have been shown to be preferentially degraded by the nonsense-mediated mRNA decay pathway (NMD). 22 To establish the relative b-galactosidase and luciferase activities, expressed in equimolar amounts, we also constructed control plasmids in which each stop mutation was replaced by the sense codon found in the wildtype gene.…”

Section: Quantification Of Readthrough Levels In Nih3t3 Cellsmentioning

confidence: 99%

“…A good candidate is the NMD pathway, which might potentiate the antibiotic effect by stabilization of the message read by ribosomes. 22 Similarly, other mechanisms like protein stability and accumulation might collectivelly participate to potentiate the primary translational effect of gentamicin. Finally, gentamicin may also affect gene expression at other levels than translation.…”

Section: Different Rules Govern Basal and Induced Readthroughmentioning

confidence: 99%

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

et al. 2004

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The suppression levels induced by gentamicin on premature stop codons, caused by primary nonsense mutations found in muscular dystrophy patients, were assessed using a very sensitive dual reporter gene assay. Results show that: (i) the effect of gentamicin on readthrough is similar in cultured cells and in vivo in murine skeletal muscle; (ii) a wide variability of readthrough efficiency is obtained, depending on the mutation tested; (iii) due to the complexity of readthrough regulation, efficiency cannot be predicted by the nucleotide context of the stop codon; (iv) only a minority of premature stop codons found in patients show a significant level of readthrough, and would thus be amenable to this pharmacological treatment, given our present understanding of the problem. These results probably provide an explanation for the relative failure of clinical trials reported to date using gentamicin to treat diseases due to premature stop codons, and emphasize that preliminary assays in cell culture provide valuable information concerning the potential efficiency of pharmacological treatments.

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RNA surveillance: unforeseen consequences for gene expression, inherited genetic disorders and cancer

Cited by 361 publications

References 51 publications

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Abnormal vertebral segmentation and the notch signaling pathway in man

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

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