TNKS

Official Full Name

tankyrase

Organism

Homo sapiens

GeneID

8658

Background

Enables NAD+-protein poly-ADP-ribosyltransferase activity; histone binding activity; and zinc ion binding activity. Involved in several processes, including positive regulation of canonical Wnt signaling pathway; post-translational protein modification; and regulation of chromosome organization. Acts upstream of or within peptidyl-serine phosphorylation and peptidyl-threonine phosphorylation. Located in several cellular components, including chromosome, telomeric region; mitotic spindle pole; and nucleus. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

TIN1; ARTD5; PARPL; TINF1; TNKS1; pART5; PARP5A; PARP-5a;

Bio Chemical Class

Glycosyltransferases

Protein Sequence

MAASRRSQHHHHHHQQQLQPAPGASAPPPPPPPPLSPGLAPGTTPASPTASGLAPFASPRHGLALPEGDGSRDPPDRPRSPDPVDGTSCCSTTSTICTVAAAPVVPAVSTSSAAGVAPNPAGSGSNNSPSSSSSPTSSSSSSPSSPGSSLAESPEAAGVSSTAPLGPGAAGPGTGVPAVSGALRELLEACRNGDVSRVKRLVDAANVNAKDMAGRKSSPLHFAAGFGRKDVVEHLLQMGANVHARDDGGLIPLHNACSFGHAEVVSLLLCQGADPNARDNWNYTPLHEAAIKGKIDVCIVLLQHGADPNIRNTDGKSALDLADPSAKAVLTGEYKKDELLEAARSGNEEKLMALLTPLNVNCHASDGRKSTPLHLAAGYNRVRIVQLLLQHGADVHAKDKGGLVPLHNACSYGHYEVTELLLKHGACVNAMDLWQFTPLHEAASKNRVEVCSLLLSHGADPTLVNCHGKSAVDMAPTPELRERLTYEFKGHSLLQAAREADLAKVKKTLALEIINFKQPQSHETALHCAVASLHPKRKQVTELLLRKGANVNEKNKDFMTPLHVAAERAHNDVMEVLHKHGAKMNALDTLGQTALHRAALAGHLQTCRLLLSYGSDPSIISLQGFTAAQMGNEAVQQILSESTPIRTSDVDYRLLEASKAGDLETVKQLCSSQNVNCRDLEGRHSTPLHFAAGYNRVSVVEYLLHHGADVHAKDKGGLVPLHNACSYGHYEVAELLVRHGASVNVADLWKFTPLHEAAAKGKYEICKLLLKHGADPTKKNRDGNTPLDLVKEGDTDIQDLLRGDAALLDAAKKGCLARVQKLCTPENINCRDTQGRNSTPLHLAAGYNNLEVAEYLLEHGADVNAQDKGGLIPLHNAASYGHVDIAALLIKYNTCVNATDKWAFTPLHEAAQKGRTQLCALLLAHGADPTMKNQEGQTPLDLATADDIRALLIDAMPPEALPTCFKPQATVVSASLISPASTPSCLSAASSIDNLTGPLAELAVGGASNAGDGAAGTERKEGEVAGLDMNISQFLKSLGLEHLRDIFETEQITLDVLADMGHEELKEIGINAYGHRHKLIKGVERLLGGQQGTNPYLTFHCVNQGTILLDLAPEDKEYQSVEEEMQSTIREHRDGGNAGGIFNRYNVIRIQKVVNKKLRERFCHRQKEVSEENHNHHNERMLFHGSPFINAIIHKGFDERHAYIGGMFGAGIYFAENSSKSNQYVYGIGGGTGCPTHKDRSCYICHRQMLFCRVTLGKSFLQFSTMKMAHAPPGHHSVIGRPSVNGLAYAEYVIYRGEQAYPEYLITYQIMKPEAPSQTATAAEQKT

Open

Disease

Ovarian cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

The TNKS (Tankyrase) gene is located on human chromosome 8p23.1 and encodes a multifunctional enzyme belonging to the poly(ADP-ribose) polymerase (PARP) superfamily. Alternative splicing of this gene generates multiple transcripts, with the main protein product having a molecular weight of approximately 142 kDa. TNKS protein contains several characteristic domains: an N-terminal HPS (homopolymeric sequence) domain mediating polymerization, an ANK (ankyrin repeat) domain responsible for protein interactions, a SAM (sterile alpha motif) domain involved in subcellular localization, and a C-terminal PARP domain that catalyzes ADP-ribosylation (PARsylation) of target proteins. In the human genome, there are two paralogues, TNKS1 (PARP5A) and TNKS2 (PARP5B), which share about 85% amino acid sequence homology but differ in tissue distribution and function. TNKS1 is broadly expressed across multiple tissues, whereas TNKS2 shows higher expression in the nervous system.

Figure 1. Structure of tankyrase 1 and 2. (Mukai T, et al., 2019)

TNKS is unique in its ability to form supramolecular complexes. The HPS domain enables TNKS to assemble into elongated filamentous structures, significantly enhancing its PARP catalytic activity. The ANK domain contains 24 ankyrin repeats forming a helical structure, providing multiple binding interfaces for interaction with proteins that contain specific motifs, such as RxxPDG. This multidomain architecture allows TNKS to act as a scaffold protein, organizing multiple signaling molecules into functional complexes. Subcellular localization of TNKS includes telomeres, centrosomes, the Golgi apparatus, and nuclear pore complexes, where it participates in chromosome stability, mitotic regulation, and vesicle trafficking.

Catalytic Activity and Regulatory Mechanisms

TNKS catalytic activity is tightly regulated. Its PARP domain mediates NAD+-dependent PARsylation, transferring linear or branched ADP-ribose polymers to glutamate residues of target proteins. This post-translational modification often alters protein function and promotes recognition by ubiquitin ligases, leading to degradation. TNKS can also undergo auto-PARsylation, providing negative feedback on its activity. Its function is further modulated by subcellular localization and protein interactions. At telomeres, TNKS interacts with TRF1 to regulate telomere length, while in the Wnt signaling pathway, TNKS binds to Axin to stabilize β-catenin.

Evolutionary analysis shows TNKS is highly conserved in vertebrates, indicating its essential biological roles. Homologues exist in Drosophila and C. elegans, albeit with simpler structures. Human TNKS also contains multiple single-nucleotide polymorphisms (SNPs) linked to disease susceptibility, highlighting its relevance in pathophysiology.

Molecular Functions and Signaling Networks

As a multidomain scaffold protein and PARP enzyme, TNKS exerts core regulatory roles in numerous cellular processes. Its most prominent function is the modulation of the Wnt/β-catenin signaling pathway, critical for embryonic development and cancer. Under basal conditions, β-catenin is phosphorylated by a destruction complex comprising Axin, APC, CK1, and GSK3β, targeting it for ubiquitination and proteasomal degradation. TNKS binds Axin through its ANK domain and catalyzes its PARsylation. PARsylated Axin is recognized by the E3 ubiquitin ligase RNF146, leading to its degradation. Axin degradation destabilizes the destruction complex, allowing β-catenin to translocate into the nucleus and activate downstream gene transcription. TNKS thus acts as a positive regulator of Wnt signaling.

TNKS also contributes to telomere maintenance through interaction with TRF1. PARsylation of TRF1 facilitates its ubiquitination and degradation, relieving inhibition of telomerase access to telomeres. This regulation is limited in normal somatic cells but enhanced in stem cells and cancer cells, promoting telomere elongation and cellular immortalization. Additionally, TNKS participates in centrosome maturation during early mitosis by PARsylating proteins such as CEP170 and HEPACAM2, ensuring proper spindle assembly.

Beyond these roles, TNKS regulates metabolic processes, including vesicular transport of the glucose transporter GLUT4. In insulin-stimulated cells, TNKS interacts with IRAP to promote GLUT4 translocation to the plasma membrane. In degenerative diseases such as osteoarthritis, TNKS responds to mechanical stress by activating Wnt/β-catenin and NF-κB signaling, inducing matrix-degrading enzymes, and promoting extracellular matrix breakdown. TNKS also participates in DNA damage response and proteasome regulation, modifying histones and repair proteins to facilitate non-homologous end joining (NHEJ) and enhancing proteasome activity to clear misfolded proteins.

Figure 2. PARP1-dependent pro-atherogenic pathways elicited by oxidized lipid molecules in atherosclerosis. (Szántó M, et al., 2021)

Role in Disease

TNKS plays key roles in tumorigenesis, degenerative disorders, and fibrotic diseases. Its overexpression in cancers can abnormally activate Wnt/β-catenin signaling, promoting tumor growth and metastasis. In osteoarthritis, TNKS mediates mechanical stress-induced cartilage degeneration by targeting transcription factors and matrix components for degradation, enhancing catabolic signaling. In fibrotic diseases, TNKS modulates fibroblast activation and TGF-β signaling, contributing to tissue fibrosis. TNKS also affects insulin signaling in metabolic disorders and is implicated in neurodegenerative diseases through modification of proteins such as tau and PARK2, linking it to Alzheimer's and Parkinson's pathology.

Therapeutic Targeting and Challenges

TNKS has emerged as a therapeutic target in cancer, osteoarthritis, fibrosis, and metabolic disorders. Small molecule inhibitors are the main strategy, with compounds such as XAV939, G007-LK, and RK-287107 demonstrating high selectivity and efficacy. TNKS inhibitors can modulate Wnt signaling, restore cartilage homeostasis, reduce fibrotic deposition, and enhance anticancer immune responses. Novel approaches include tissue-targeted delivery, controlled-release formulations, and next-generation selective allosteric inhibitors. Challenges remain, including functional redundancy between TNKS1 and TNKS2, potential off-target effects on normal tissue homeostasis, and long-term consequences of telomere shortening and stem cell depletion. Continued understanding of TNKS biology and technological innovation offers promising avenues for therapeutic intervention across multiple disease contexts.

Reference

Szántó M, Gupte R, Kraus WL, et al. PARPs in lipid metabolism and related diseases. Prog Lipid Res. 2021 Nov;84:101117.
Ouelaa-Benslama R, Emami S. Pinworm and TNKS inhibitors, an eccentric duo to derail the oncogenic WNT pathway. Clin Res Hepatol Gastroenterol. 2011 Sep;35(8-9):534-8.
Jessop M, Broadway BJ, Miller K, et al. Regulation of PARP1/2 and the tankyrases: emerging parallels. Biochem J. 2024 Sep 4;481(17):1097-1123.
Sagathia V, Patel C, Beladiya J, et al. Tankyrase: a promising therapeutic target with pleiotropic action. Naunyn Schmiedebergs Arch Pharmacol. 2023 Dec;396(12):3363-3374.
Mukai T, Fujita S, Morita Y. Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2. Cells. 2019 Feb 22;8(2):195.

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