2014
DOI: 10.1038/nsmb.2858
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Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans

Abstract: Myotonic dystrophy disorders are caused by expanded CUG repeats in non-coding regions. To reveal mechanisms of CUG repeat pathogenesis we used C. elegans expressing CUG repeats to identify gene inactivations that modulate CUG repeat toxicity. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and modulate formation of nuclear RNA foci by CUG repeats. These genes regulated CUG repeat-induced toxicity through distinct mechanisms including RNA export and RNA … Show more

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Cited by 24 publications
(42 citation statements)
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“…levels, unbiased screens expedite the discovery of new compounds and can identify unanticipated cellular targets. Small-molecule and genetic screens have been employed in the search for therapeutics as well as to inform interesting new biology associated with the CTG repeat expansion (13,(31)(32)(33)(34)(35)(36). However, a CTG repeat-selective screen targeting r(CUG) EXP production and/or stability in cells has not been reported.…”
Section: Significancementioning
confidence: 99%
“…levels, unbiased screens expedite the discovery of new compounds and can identify unanticipated cellular targets. Small-molecule and genetic screens have been employed in the search for therapeutics as well as to inform interesting new biology associated with the CTG repeat expansion (13,(31)(32)(33)(34)(35)(36). However, a CTG repeat-selective screen targeting r(CUG) EXP production and/or stability in cells has not been reported.…”
Section: Significancementioning
confidence: 99%
“…While direct evidence for what drives these transcript level changes is missing, several attractive hypotheses exist including depletion of other MBNL paralogues and increase in CELF1 activity. CUG exp RNA also disrupts other cellular processes including “leaching” of transcription factors (Ebralidze et al, ), abnormal DNA methylation (Lopez Castel et al, ), processing of repeats into small RNAs that produce unwanted gene silencing (Krol et al, ), activation of PKC‐dependent signaling pathways (Kuyumcu‐Martinez et al, ), bidirectional transcription (Nakamori et al, ), repeat associated non‐ATG translation (Zu et al, ), microRNA deregulation (Perbellini et al, ; Rau et al, ; Fernandez‐Costa et al, ; Kalsotra et al, ), and nonsense‐mediated decay pathway (Garcia et al, ). Some of these splicing‐independent abnormalities are discussed below.…”
Section: Pathology Beyond Splicingmentioning
confidence: 99%
“…The nonsense‐mediated decay (NMD) pathway is a surveillance mechanism that detects mRNA with premature stop codons and targets them for degradation to prevent the expression of potentially toxic truncated proteins (Chang et al, ). RNAi silencing of smg‐2, an RNA helicase component of the NMD pathway, in a DM1 C. elegans model causes an increase in CUG repeat containing mRNA (Garcia et al, ). Mutations in other NMD pathway genes, specifically smg‐1 and smg‐6, also resulted in a similar increase in CUG repeat RNA.…”
Section: Pathology Beyond Splicingmentioning
confidence: 99%
“…Collectively the data argue in favor of the temperature-sensitive dose-dependent proteotoxicity model involving the depletion of the chaperone system capacity required to buffer the combined load of the aggregation-prone cargo. Given the preliminary nature of our report, presently we can not conclusively exclude the other pathogenesis mediators, such us postulated RNA-repeat toxicity pathways (Nalavade et al 2013;Garcia et al 2014;Marti 2016), imposes on and contributes to the overall combined proteopathy phenotype (Li et al 2008). We note however, that overall length of expanded polyQ encoding (CAG) repeats used in our model might not suffice for significant RNArepeat toxicity (Finkbeiner 2011).…”
Section: Discussionmentioning
confidence: 84%