Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts

Toulouse, André; Au-Yeung, Faith; Gaspar, Cláudia; Roussel, Julie; Dion, Patrick A.; Rouleau, Guy

doi:10.1093/hmg/ddi299

Cited by 55 publications

(52 citation statements)

References 42 publications

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“…5C). Although previously frame shifting has been suggested to result in hybrid polyGln-polyAla and polyGlnpolySer proteins in spinocerebellar ataxia type 3 (SCA3) and Huntington disease (14,15), our data demonstrate that frame shifting is rare, and an out-of-frame ATG initiation codon is not required for polyAla or polySer expression.…”

Section: * N S a A A A A A A A A A A A A A A A A A R A A A A A A A contrasting

confidence: 78%

Non-ATG–initiated translation directed by microsatellite expansions

Zu¹,

Gibbens²,

Doty³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

786

1,022

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Trinucleotide expansions cause disease by both protein-and RNAmediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.T ranslation of mRNA into protein is an exquisitely regulated, almost error-free process. Well-established rules of translational initiation have been used as a cornerstone in biology to understand gene expression and to predict the consequences of disease-causing mutations (1). For microsatellite expansion disorders, mutations within or outside ATG-initiated ORFs are thought to cause disease either by protein gain-of-function, protein loss-of-function, or RNA gain-of-function mechanisms (2, 3).Microsatellite expansion mutations that express polyglutamine (polyGln) expansion proteins include Huntington disease (Huntingtin, HD), spinal bulbar muscular atrophy, and spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17. Since the discovery of these CAG·CTG expansion mutations, efforts to understand disease mechanisms have focused on elucidating the molecular effects of the polyGln proteins expressed from these loci. Although these polyGln expansion proteins bear no similarity to each other apart from the polyGln tract, a hallmark of these diseases is protein accumulation and aggregation in nuclear or cytoplasmic inclusions. Surprisingly, although the polyGln expansion proteins are widely expressed in the CNS and other tissues, only restricted populations of neurons are vulnerable in each disease (3).Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are the best-characterized examples of RNA-mediated expansion disorders (2). The mutation causing DM1 is a CTG-repeat expansion located in the 3′ UTR of the dystrophia myotonica-protein kinase (DMPK) gene. Although DM1 can be clinically more severe than DM2, the discovery of the DM2 mutation and several mouse models provide strong support that many features of these diseases result from RNA gain-of-function effects in which the dysregulation of RNA-binding proteins is mediated by the expression of CUG and CCUG transcripts (4). Additionally, RNA gain-of-function effects have been reported for CGG and CAG expansion RNAs (5, 6).Both RNA and protein mechanisms appear to operate...

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Section: * N S a A A A A A A A A A A A A A A A A A R A A A A A A A contrasting

confidence: 78%

Non-ATG–initiated translation directed by microsatellite expansions

Zu¹,

Gibbens²,

Doty³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

786

1,022

View full text Add to dashboard Cite

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“…The emerging evidence for alternative products generated through repeat-associated non-ATG translation (3,43), by translational Ϫ1 frameshifting (5,6,10), or, as revealed here, by translational ϩ1 frameshifting suggests that dynamic reprogramming of translation to generate alternative products from one gene is more common than previously appreciated. The toxicity of HttQ proteins is mainly attributed to nuclearly localized species (44,45).…”

Section: Discussionmentioning

confidence: 68%

“…Expanded CAG repeat stretches, implicated in CAG repeat or polyglutamine (polyQ) 4 diseases (2), mediate Ϫ1 translational frameshifting, although the underlying mechanisms differ depending on the context surrounding repeat runs (5,6,10). Our earlier work shows that pathological expansion of the CAG repeats (Ͼ35 consecutive CAG codons) in huntingtin (Htt) exon 1, implicated in Huntington disease, involves stochastic Ϫ1 frameshifting within the CAG stretch that is triggered by limitation of the charged cognate glutaminyl-tRNA Gln CUG, although uncharged tRNA Gln CUG is plentiful (5).…”

mentioning

confidence: 99%

“…In partial contrast, for the stochastic Ϫ1 frameshifting in decoding the expanded CAG run in the SCA3 gene associated with spinocerebellar ataxia type 3, an mRNA structure formed by the CAG repeats has been proposed as a major stimulatory component of the Ϫ1 frameshifting. A depletion of glutaminyl-tRNA Gln CUG is likely to be involved, as alternating bicodon CAA CAG repeats read by different tRNAs but with not too distant propensity to form secondary structure do not exhibit Ϫ1 frameshifting (6,10).…”

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confidence: 99%

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An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting

Saffert

Adamla

Schieweck

et al. 2016

Journal of Biological Chemistry

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Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the ؊1 or ؉1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic ؉1 frameshift to generate from the CAG repeat a transframe AGC repeat-encoded product. This ؉1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical ؉1 shift site, UUC C at the 5 end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the ؉1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The ؉1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1.

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“…However, careful examination of poly-Ala-expanded alleles reveals similarities between their pattern and the pattern of minisatellite rearrangements during meiotic recombination (see "Molecular mechanisms involved in mini-and microsatellite expansions" below), suggesting that gene conversion (with or without crossover) could be involved in polyalanine expansions. Interestingly, it was shown that polyglutamine tracts were often mistranslated, leading to polyalanine tracts by a ribosomal Ϫ1 frameshift (159,500).…”

Section: Trinucleotide Repeat Expansionsmentioning

confidence: 99%

Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes

Richard

Kerrest

Dujon

2008

Microbiol Mol Biol Rev

491

411

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SUMMARY Repeated elements can be widely abundant in eukaryotic genomes, composing more than 50% of the human genome, for example. It is possible to classify repeated sequences into two large families, “tandem repeats” and “dispersed repeats.” Each of these two families can be itself divided into subfamilies. Dispersed repeats contain transposons, tRNA genes, and gene paralogues, whereas tandem repeats contain gene tandems, ribosomal DNA repeat arrays, and satellite DNA, itself subdivided into satellites, minisatellites, and microsatellites. Remarkably, the molecular mechanisms that create and propagate dispersed and tandem repeats are specific to each class and usually do not overlap. In the present review, we have chosen in the first section to describe the nature and distribution of dispersed and tandem repeats in eukaryotic genomes in the light of complete (or nearly complete) available genome sequences. In the second part, we focus on the molecular mechanisms responsible for the fast evolution of two specific classes of tandem repeats: minisatellites and microsatellites. Given that a growing number of human neurological disorders involve the expansion of a particular class of microsatellites, called trinucleotide repeats, a large part of the recent experimental work on microsatellites has focused on these particular repeats, and thus we also review the current knowledge in this area. Finally, we propose a unified definition for mini- and microsatellites that takes into account their biological properties and try to point out new directions that should be explored in a near future on our road to understanding the genetics of repeated sequences.

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Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts

Cited by 55 publications

References 42 publications

Non-ATG–initiated translation directed by microsatellite expansions

Non-ATG–initiated translation directed by microsatellite expansions

An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting

Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes

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