ZRSR2

Gene Summary

Gene:ZRSR2; zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2
Aliases: URP, ZC3H22, U2AF1L2, U2AF1RS2, U2AF1-RS2
Location:Xp22.2
Summary:This gene encodes an essential splicing factor. The encoded protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3' splice site in pre-mRNA splicing, and may play a role in network interactions during spliceosome assembly. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (8)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Epigenetics
  • Phenotype
  • Signal Transduction
  • Spliceosomes
  • High-Throughput Nucleotide Sequencing
  • Biomarkers, Tumor
  • Ribonucleoproteins
  • DNA Mutational Analysis
  • Neoplasm Recurrence, Local
  • Phosphoproteins
  • Haematological Malignancies
  • Nuclear Proteins
  • Antigens, Nuclear
  • Neoplastic Cell Transformation
  • Second Primary Cancer
  • Survival Rate
  • DNA Methylation
  • RNA Splicing
  • Chromatin
  • Chronic Myelogenous Leukemia
  • Ribonucleoprotein, U2 Small Nuclear
  • RNA Splicing Factors
  • Single Nucleotide Polymorphism
  • Adolescents
  • Protein Kinase Inhibitors
  • Young Adult
  • Mutation
  • X Chromosome
  • Acute Myeloid Leukaemia
  • Follow-Up Studies
  • ASXL1
  • DNA Repair
  • BCOR
  • Neoplasm Proteins
  • Fusion Proteins, bcr-abl
  • Splicing Factor U2AF
  • Transcription
  • Myelodysplastic Syndromes
  • ZRSR2
  • Serine-Arginine Splicing Factors
  • Philadelphia Chromosome
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. 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).

Latest Publications: ZRSR2 (cancer-related)

Neumann M, Vosberg S, Schlee C, et al.
Mutational spectrum of adult T-ALL.
Oncotarget. 2015; 6(5):2754-66 [PubMed] Free Access to Full Article Related Publications
Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.

Jhanwar SC
Genetic and epigenetic pathways in myelodysplastic syndromes: A brief overview.
Adv Biol Regul. 2015; 58:28-37 [PubMed] Related Publications
Myelodysplastic syndromes (MDS) are a highly heterogenous group of hematopoietic tumors, mainly due to variable clinical features and diverse set of cytogenetic, molecular genetic and epigenetic lesions. The major clinical features of MDS are ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemias, which in turn is most likely determined by specific genetic abnormalities and other presenting hematologic features. The risk of developing MDS is relatively higher in some genetic syndromes such as Fanconi anemia and receipt of chemotherapy and radiation treatment. In recent years a significant progress has occurred and a vast literatures has become available including the spectrum of cytogenetic abnormalities, gene mutations relating to RNA splicing machinery, epigenetic regulation of gene expression and signaling pathways associated with MDS pathogenesis, which have provided opportunities to understand the molecular mechanisms as well as employ targeted therapeutic approaches to treat MDS. The cytogenetic abnormalities detected in MDS varies from a single abnormality to complex karyotype not easily amenable to conventional cytogenetic analysis. In such cases, array based high resolution genomic analysis detected abnormalities, which are diagnostic as well as prognostic. The most common driver gene mutations detected in patients with MDS include RNA splicing (SF3B1,SRSF2,U2F1,ZRSR2), DNA methylation (TET2,DNMT3A,IDH1/IDH2), chromatin modification (ASXL1,EZH2), transcription regulation (RUNX1,BCOR) and DNA repair control p53. A small subset of MDS arise due to deregulation of RAS pathway, mainly due to NRAS/KRAS/NF1 mutations. Identification of these mutations and pathways have provided opportunities for oncologists to target these patients with specific therapies. Several drugs which either target the spliceosome, oncogenic RAS signaling, or hypomethylating agents have been employed to successfully treat MDS patients.

Wong JJ, Lau KA, Pinello N, Rasko JE
Epigenetic modifications of splicing factor genes in myelodysplastic syndromes and acute myeloid leukemia.
Cancer Sci. 2014; 105(11):1457-63 [PubMed] Free Access to Full Article Related Publications
Somatic mutations in splicing factor genes have frequently been reported in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Although aberrant epigenetic changes are frequently implicated in blood cancers, their direct role in suppressing one or both alleles of critical splicing factors has not been previously examined. Here, we examined promoter DNA hypermethylation of nine splicing factors, SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, HNRNPR, MATR3, ZFR, and YBX3 in 10 leukemic cell lines and 94 MDS or AML patient samples from the Australasian Leukemia and Lymphoma Group Tissue Bank. The only evidence of epigenetic effects was hypermethylation of the YBX3 promoter in U937 cells in conjunction with an enrichment of histone marks associated with gene silencing. In silico analysis of DNA methylation data for 173 AML samples generated by the Cancer Genome Atlas Research Network revealed promoter hypermethylation of the gene encoding Y box binding protein 3, YBX3, in 11/173 (6.4%) AML cases, which was significantly associated with reduced mRNA expression (P < 0.0001). Hypermethylation of the ZRSR2 promoter was also detected in 7/173 (4%) cases but was not associated with decreased mRNA expression (P = 0.1204). Hypermethylation was absent at the promoter of seven other splicing factor genes in all cell lines and patient samples examined. We conclude that DNA hypermethylation does not frequently silence splicing factors in MDS and AML. However, in the case of YBX3, promoter hypermethylation-induced downregulation may contribute to the pathogenesis or maintenance of AML.

Schmidt M, Rinke J, Schäfer V, et al.
Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.
Leukemia. 2014; 28(12):2292-9 [PubMed] Related Publications
To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.

Yoshida K, Ogawa S
Splicing factor mutations and cancer.
Wiley Interdiscip Rev RNA. 2014 Jul-Aug; 5(4):445-59 [PubMed] Related Publications
Recent advances in high-throughput sequencing technologies have unexpectedly revealed that somatic mutations of splicing factor genes frequently occurred in several types of hematological malignancies, including myelodysplastic syndromes, other myeloid neoplasms, and chronic lymphocytic leukemia. Splicing factor mutations have also been reported in solid cancers such as breast and pancreatic cancers, uveal melanomas, and lung adenocarcinomas. These mutations were heterozygous and mainly affected U2AF1 (U2AF35), SRSF2 (SC35), SF3B1 (SF3B155 or SAP155), and ZRSR2 (URP), which are engaged in the initial steps of RNA splicing, including 3' splice-site recognition, and occur in a large mutually exclusive pattern, suggesting a common impact of these mutations on RNA splicing. In this study, splicing factor mutations in various types of cancers, their functional/biological effects, and their potential as therapeutic targets have been reviewed.

Cazzola M, Della Porta MG, Malcovati L
The genetic basis of myelodysplasia and its clinical relevance.
Blood. 2013; 122(25):4021-34 [PubMed] Free Access to Full Article Related Publications
Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed.

Larsson CA, Cote G, Quintás-Cardama A
The changing mutational landscape of acute myeloid leukemia and myelodysplastic syndrome.
Mol Cancer Res. 2013; 11(8):815-27 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Over the past few years, large-scale genomic studies of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have unveiled recurrent somatic mutations in genes involved in epigenetic regulation (DNMT3A, IDH1/2, TET2, ASXL1, EZH2 and MLL) and the spliceosomal machinery (SF3B1, U2AF1, SRSF2, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1). The identification of these mutations and their impact on prognostication has led to improvements in risk-stratification strategies and has also provided new potential targets for the treatment of these myeloid malignancies. In this review, we discuss the most recently identified genetic abnormalities described in MDS and AML and appraise the current status quo of the dynamics of acquisition of mutant alleles in the pathogenesis of AML, during the transformation from MDS to AML, and in the context of relapse after conventional chemotherapy.
IMPLICATIONS: Identification of somatic mutations in AML and MDS suggests new targets for therapeutic development.

Damm F, Kosmider O, Gelsi-Boyer V, et al.
Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes.
Blood. 2012; 119(14):3211-8 [PubMed] Related Publications
A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

Acero Sanchez JL, Henry OY, Mairal T, et al.
Colorimetric quantification of mRNA expression in rare tumour cells amplified by multiple ligation-dependent probe amplification.
Anal Bioanal Chem. 2010; 397(6):2325-34 [PubMed] Related Publications
An enzyme-linked oligonucleotide assay (ELONA) for quantification of mRNA expression of five genes involved in breast cancer, extracted from isolated rare tumour cells and amplified by multiplex ligation-dependent probe amplification (MLPA) is presented. In MLPA, a multiplex oligonucleotide ligation assay is combined with a PCR reaction in which all ligation products are amplified by use of a single primer pair. Biotinylated probes complementary to each of the target sequences were immobilised on the surface of a streptavidin-coated microtitre plate and exposed to single-stranded MLPA products. A universal reporting probe sequence modified with horseradish peroxidase (URP-HRP) and complementary to a universal primer used during the MLPA step was further added to the surface-bound duplex as a reporter probe. Simultaneous addition of anchoring probe and target, followed by addition of reporter probe, rather than sequential addition, was achieved with no significant effect on sensitivity and limits of detection, but considerably reduced the required assay time. Detection limits as low as 20 pmol L(-1), with an overall assay time of 95 min could be achieved with negligible cross-reactivity between probes and non-specific targets present in the MLPA-PCR product. The same MLPA-PCR product was analysed using capillary electrophoresis, the technique typically used for analysis of MLPA products, and good correlation was observed. The assay presented is easy to carry out, relatively inexpensive, rapid, does not require sophisticated instrumentation, and enables quantitative analysis, making it very promising for the analysis of MLPA products.

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Cite this page: Cotterill SJ. ZRSR2, Cancer Genetics Web: http://www.cancer-genetics.org/ZRSR2.htm Accessed:

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