Perlman Syndrome: Overgrowth, Wilms Tumor Predisposition and <i>DIS3L2</i>

Morris, Mark R.; Astuti, Dewi; Maher, Eamonn R.

doi:10.1002/ajmg.c.31358

Cited by 43 publications

(35 citation statements)

References 62 publications

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“…Mutations in DIS3L2 are involved in the Perlman overgrowth and Wilms’ tumor predisposition syndrome (Astuti et al, 2012). Moreover, DIS3L2 mutations or deletions have been reported in sporadic Wilms’ tumors (Astuti et al, 2012; Morris et al, 2013; Wegert et al, 2015). Despite these strong links between DIS3L2 deficiency and human disease, very little is known about the role of Dis3l2 in RNA regulation and specifically the identity of its direct targets has so far remained elusive.…”

Section: Introductionmentioning

confidence: 99%

Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs

et al. 2016

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SUMMARY Mutations in the 3′-5′ exonuclease DIS3L2 are associated with Perlman syndrome and hypersusceptibility to Wilms’ tumorigenesis. Previously, we found that Dis3l2 specifically recognizes and degrades uridylated pre-let-7 microRNA. However, the widespread relevance of Dis3l2-mediated decay of uridylated substrates remains unknown. Here we applied an unbiased RNA immunoprecipitation strategy to identify Dis3l2 targets in mouse embryonic stem cells. The disease-associated long noncoding RNA (lncRNA) Rmrp, 7SL, as well as several other Pol III-transcribed noncoding RNAs (ncRNAs) were among the most highly enriched Dis3l2-bound RNAs. 3′-uridylated Rmrp, 7SL, and snRNA species were highly stabilized in the cytoplasm of Dis3l2-depleted cells. Deep sequencing analysis of Rmrp 3′ ends revealed extensive oligouridylation mainly on transcripts with imprecise ends. We implicate the TUTases Zcchc6/11 in the uridylation of these ncRNAs, and biochemical reconstitution assays demonstrate the sufficiency of TUTase-Dis3l2 for Rmrp decay. This establishes Dis3l2-Mediated Decay (DMD) as a quality control pathway that eliminates aberrant ncRNAs.

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Section: Introductionmentioning

confidence: 99%

Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs

et al. 2016

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“…While HeLa cells are perhaps not the most physiologically relevant cell line, Dis3L2 knockdown was also shown to increase cell number with a selection of cell-cycle related transcripts affected (Astuti et al, 2012). The phenotypes are also strikingly similar to two human overgrowth disorders, Perlman Syndrome and Wilms' Tumor, which have been associated with Dis3L2 mutations suggesting a crucial and conserved function (Astuti et al, 2012;Morris, Astuti, & Maher, 2013).…”

Section: Phenotypes Resulting From Loss Of Dis3l2mentioning

confidence: 87%

Regulation of cytoplasmic RNA stability: Lessons from Drosophila

Towler

Newbury

2018

WIREs RNA

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The process of RNA degradation is a critical level of regulation contributing to the control of gene expression. In the last two decades a number of studies have shown the specific and targeted nature of RNA decay and its importance in maintaining homeostasis. The key players within the pathways of RNA decay are well conserved with their mutation or disruption resulting in distinct phenotypes as well as human disease. Model organisms including Drosophila melanogaster have played a substantial role in elucidating the mechanisms conferring control over RNA stability. A particular advantage of this model organism is that the functions of ribonucleases can be assessed in the context of natural cells within tissues in addition to individual immortalized cells in culture. Drosophila RNA stability research has demonstrated how the cytoplasmic decay machines, such as the exosome, Dis3L2 and Xrn1, are responsible for regulating specific processes including apoptosis, proliferation, wound healing and fertility. The work discussed here has begun to identify specific mRNA transcripts that appear sensitive to specific decay pathways representing mechanisms through which the ribonucleases control mRNA stability. Drosophila research has also contributed to our knowledge of how specific RNAs are targeted to the ribonucleases including AU rich elements, miRNA targeting and 3' tailing. Increased understanding of these mechanisms is critical to elucidating the control elicited by the cytoplasmic ribonucleases which is relevant to human disease. This article is categorized under: RNA in Disease and Development > RNA in Development RNA Turnover and Surveillance > Regulation of RNA Stability RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms.

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“…Histological examinations reveal nephroblastomatosis, which is an important precursor for Wilms' Tumour. Germline mutations in these children include deletions of either exon 6, 9 and/or 19 which are consistent with a loss of function of DIS3L2 [25,29].…”

Section: Human Diseases Associated With Dis3l2mentioning

confidence: 87%

“…Mutations in DIS3L2 have also been associated with sporadic occurrence of Wilms' Tumour, a kidney cancer also referred to as a nephroblastoma [25,28,29]. Wilms' Tumour results from the failure of groups of kidney cells to mature and differentiate, instead undergoing continuous proliferation.…”

Section: Human Diseases Associated With Dis3l2mentioning

confidence: 99%

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease

Pashler

Towler

Jones

et al. 2016

Biochemical Society Transactions

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RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases which are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions.

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Perlman Syndrome: Overgrowth, Wilms Tumor Predisposition and DIS3L2

Cited by 43 publications

References 62 publications

Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs

Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs

Regulation of cytoplasmic RNA stability: Lessons from Drosophila

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease

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