TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase)

2011-06-01   Yury Shebzukhov  , Sergei Nedospasov  

German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany (YS, SN); Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (SN)

Identity

HGNC
LOCATION
8p23.1
LOCUSID
ALIAS
ARTD5,PARP-5a,PARP5A,PARPL,TIN1,TINF1,TNKS1,pART5
FUSION GENES

DNA/RNA

Description

Spans 226410 bp, 27 exons.

Transcription

9599 bp long mRNA, containing 3984 bp long ORF.

Proteins

Atlas Image
TNKS protein. HPS: region containing homopolymeric runs of His, Pro, and Ser; ANK: ankyrin domain; SAM: multimerization domain homologous to the sterile alpha motif; PARP: PARP catalytic domain.

Description

Isoform 1 (1327 amino acids) contains region with homopolymeric runs of His, Pro, and Ser (HPS domain, aa 1-181), 15 ankyrin repeats (ANK 1 to 15, aa 215-934), multimerization domain homologous to the sterile alpha motif (SAM domain, aa 1030-1089) and PARP catalytic domain (aa 1112-1317). Isoform 2 (643 amino acids) contains only HPS domain and 9 ANK repeats.

Expression

Ubiquitous, high expression in brain and ganglions, skin and cardiac tissue.

Localisation

Nuclear and cytoplasmic.

Function

Poly(ADP-ribosyl)ation (PARsylation) of target proteins: TNKS itself, TNKS2/TNKL, TRF1, IRAP, TAB182/TNKS1BP1, EBNA-1, Mcl-1L, Mcl-1S, NuMA, AXIN1, AXIN2.
TNKS PARsylates TRF1 (telomeric repeat-binding factor 1), a negative regulator of telomere length maintenance. PARsylated TRF1 dissociates from telomeres, enhancing telomerase-mediated telomere elongation (Smith and de Lange, 2000; Cook et al., 2002).
PARsylation of NuMA (nuclear mitotic apparatus protein) by TNKS contributes to mitotic spindle pole assembly (Sbodio and Chi, 2002).
TNKS can PARsylate Mcl-1L and Mcl-1S and inhibit their anti- and pro-apoptotic function correspondingly (Bae et al., 2003).
TNKS inhibits Epstein-Barr virus OriP function by binding and modifying Epstein-Barr nuclear antigen 1 (EBNA1) (Deng et al., 2002; Deng et al., 2005).
PARsylation activity of TNKS increases after phosphorilation by mitogen-activated protein kinase (MAPK) upon insulin stimulation (Chi and Lodish, 2000).
TNKS together with its partner IRAP enhances insulin-stimulated exocytosis of GLUT4 (Yeh et al., 2007).
TNKS PARsylates AXIN1 and AXIN2 components of beta-catenin (the Wnt pathway transcription factor) destruction complex (Huang et al., 2009).
TNKS is a target of the FANCD2, the key protein involved in development of Fanconi anemia. FANCD binds tankyrase-1 and inhibits its PARsylation at telomeres (Lyakhovich et al., 2011).

Homology

With TNKS2/TNKL.

Mutations

Somatic

Frameshift mutations are found in exons 9 and 10 in gastric and colorectal malignant tumors (Kim et al., 2011).

Implicated in

Entity name
Cancer
Note
TNKS is considered as a potential target for anticancer treatment.
Inhibition of PARP activities of TNKS blocks Wnt/beta-catenin pathway and increases efficiency of telomerase inhibitors (Seimiya et al., 2005; Huang et al., 2009; Zhang et al., 2010).
Disease
TNKS expression increased in some tumors (compared to adjacent normal tissues), including breast, bladder and gastric cancer (Gelmini et al., 2004; Gelmini et al., 2007; Poonepalli et al., 2008; Gao et al., 2011), but in other tumors, e.g. malignant glioma and colorectal cancer TNKS expression might be downregulated (Shervington et al., 2007; Shebzukhov et al., 2008), Fanconi anemia (Lyakhovich et al., 2011).

Article Bibliography

Pubmed IDLast YearTitleAuthors
124759932003Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis.Bae J et al
109882992000Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles.Chi NW et al
117397452002Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres.Cook BD et al
157952502005Inhibition of Epstein-Barr virus OriP function by tankyrase, a telomere-associated poly-ADP ribose polymerase that binds and modifies EBNA1.Deng Z et al
119317582002Telomeric proteins regulate episomal maintenance of Epstein-Barr virus origin of plasmid replication.Deng Z et al
214556372011Expression of tankyrase 1 in gastric cancer and its correlation with telomerase activity.Gao J et al
155009512004Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer.Gelmini S et al
176170282007Tankyrase-1 mRNA expression in bladder cancer and paired urine sediment: preliminary experience.Gelmini S et al
197595372009Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.Huang SM et al
213333222011Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability.Kim MS et al
213149792011Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner.Lyakhovich A et al
187205222008Telomere-mediated genomic instability and the clinico-pathological parameters in breast cancer.Poonepalli A et al
120800612002Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RXXPDG motif and is a novel tankyrase partner.Sbodio JI et al
156527472005Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.Seimiya H et al
180269512008Human tankyrases are aberrantly expressed in colon tumors and contain multiple epitopes that induce humoral and cellular immune responses in cancer patients.Shebzukhov YV et al
171969472007Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma.Shervington A et al
110691132000Tankyrase promotes telomere elongation in human cells.Smith S et al
170593882007Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase.Yeh TY et al
208116892010Inhibition of tankyrase 1 in human gastric cancer cells enhances telomere shortening by telomerase inhibitors.Zhang H et al

Other Information

Locus ID:

NCBI: 8658
MIM: 603303
HGNC: 11941
Ensembl: ENSG00000173273

Variants:

dbSNP: 8658
ClinVar: 8658
TCGA: ENSG00000173273
COSMIC: TNKS

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000173273ENST00000310430O95271
ENSG00000173273ENST00000517770H0YAW5
ENSG00000173273ENST00000518281E7EQ52
ENSG00000173273ENST00000518635A0A0C4DGE3
ENSG00000173273ENST00000520408E7EWY6
ENSG00000173273ENST00000522110E5RHD2

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by WNT in cancerREACTOMER-HSA-4791275
XAV939 inhibits tankyrase, stabilizing AXINREACTOMER-HSA-5545619
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Degradation of AXINREACTOMER-HSA-4641257
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
377419442024Tankyrase inhibition interferes with junction remodeling, induces leakiness, and disturbs YAP1/TAZ signaling in the endothelium.0
382160822024BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer.0
377419442024Tankyrase inhibition interferes with junction remodeling, induces leakiness, and disturbs YAP1/TAZ signaling in the endothelium.0
382160822024BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer.0
366034852023Effect and interaction of TNKS genetic polymorphisms and environmental factors on telomere damage in COEs-exposure workers.0
366034852023Effect and interaction of TNKS genetic polymorphisms and environmental factors on telomere damage in COEs-exposure workers.0
354500282022Deubiquitination of TNKS1 Regulates Wnt/β-Catenin to Affect the Expression of USP25 to Promote the Progression of Glioma.3
357332602022Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.12
354500282022Deubiquitination of TNKS1 Regulates Wnt/β-Catenin to Affect the Expression of USP25 to Promote the Progression of Glioma.3
357332602022Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.12
333611072021Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1.18
338112512021Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines.12
339234432021Arpin Regulates Migration Persistence by Interacting with Both Tankyrases and the Arp2/3 Complex.5
342989502021Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor.2
348766952021Tankyrase-1-mediated degradation of Golgin45 regulates glycosyltransferase trafficking and protein glycosylation in Rab2-GTP-dependent manner.8

Citation

Yury Shebzukhov ; Sergei Nedospasov

TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase)

Atlas Genet Cytogenet Oncol Haematol. 2011-06-01

Online version: http://atlasgeneticsoncology.org/gene/43534/case-report-explorer/js/lib/css/card-gene.css