|Gene:||DIS3L2; DIS3 like 3'-5' exoribonuclease 2|
|Aliases: || FAM6A, PRLMNS, hDIS3L2 |
|Summary:||The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]|
|Databases:||OMIM, HGNC, Ensembl, GeneCard, Gene|
|Protein:||DIS3-like exonuclease 2|
|Updated:||29 December, 2014|
What does this gene/protein do?
Graph generated 29 December 2014 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 29 December, 2014 using data from PubMed, MeSH and CancerIndex
Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: DIS3L2 (cancer-related)
Tian F, Yourek G, Shi X, Yang YThe development of Wilms tumor: from WT1 and microRNA to animal models.
Biochim Biophys Acta. 2014; 1846(1):180-7 [PubMed
] Related Publications
Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor.Related: Kidney Cancer WT1 Wilms' Tumour Wilms Tumour
Regulated degradation plays a major role in determining the levels of both non-coding (miRNA) and coding (mRNA) transcripts. Thus, insights into the factors and pathways that influence this process have broad, interdisciplinary implications. New findings by Malecki et al (2013), Lubas et al (2013), and Chang et al (2013) identify the protein Dis3L2 as a major player in the 3′–5′ exonucleolytic decay of transcripts. Furthermore, they demonstrate a strong connection between terminal uridylation of the RNA substrate and enzymatic activity.Related: Wilms' Tumour Wilms Tumour
Morris MR, Astuti D, Maher ERPerlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2.
Am J Med Genet C Semin Med Genet. 2013; 163C(2):106-13 [PubMed
] Related Publications
Perlman syndrome is a rare autosomal recessively inherited congenital overgrowth syndrome characterized by polyhydramnios, macrosomia, characteristic facial dysmorphology, renal dysplasia and nephroblastomatosis and multiple congenital anomalies. Perlman syndrome is associated with high neonatal mortality and, survivors have developmental delay and a high risk of Wilms tumor. Recently a Perlman syndrome locus was mapped to chromosome 2q37 and homozygous or compound heterozygous mutations were characterized in DIS3L2. The DIS3L2 gene product has ribonuclease activity and homology to the DIS3 component of the RNA exosome. It has been postulated that the clinical features of Perlman syndrome result from disordered RNA metabolism and, though the precise targets of DIS3L2 have yet to be characterized, in cellular models DIS3L2 knockdown is associated with abnormalities of cell growth and division.Related: Wilms' Tumour Wilms Tumour
The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis. Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development.Related: Wilms' Tumour Wilms Tumour
Higashimoto K, Maeda T, Okada J, et al.Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.
Eur J Hum Genet. 2013; 21(11):1316-9 [PubMed
] Free Access to Full Article Related Publications
Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR.Related: Wilms' Tumour Wilms Tumour
Nephroblastoma (Wilms' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.Related: Chromosome 9 CGH Kidney Cancer Wilms' Tumour Wilms Tumour
Astuti D, Morris MR, Cooper WN, et al.Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
Nat Genet. 2012; 44(3):277-84 [PubMed
] Related Publications