Novel insight into the function of tankyrase

Abstract

Tankyrases are multifunctional poly(ADP-ribose) polymerases that regulate a variety of cellular processes, including Wnt signaling, telomere maintenance and mitosis regulation. Tankyrases interact with target proteins and regulate their interactions and stability through poly(ADP-ribosyl) ation. In addition to their roles in telomere maintenance and regulation of mitosis, tankyrase proteins regulate tumor suppressors, including AXIN, phosphatase and tensin homolog and angiomotin. Therefore, tankyrases may be effective targets for cancer treatment. Tankyrase inhibitors could affect a variety of carcinogenic pathways that promote uncontrolled proliferation, including Wnt, AKT, yes-associated protein, telomere maintenance and mitosis regulation. Recently, novel aspects of the function and mechanism of tankyrases have been reported, and a number of tankyrase inhibitors have been identified. A combination of conventional chemotherapy agents with tankyrase inhibitors may have synergistic anticancer effects. Therefore, it is expected that more advanced and improved tankyrase inhibitors will be developed, enabling novel therapeutic strategies against cancer and other tankyrase-associated diseases. The present review discusses tankyrase function and the role of tankyrase inhibitors in the treatment of cancer.

Keywords: cancer therapy; novel tankyrase binding partners; post-translational modification; tankyrase; tankyrase inhibitors.

Figure 1.

Tankyrase function in cancer. (A) ADP-ribosylation of TRF1 by tankyrase 1 releases TRF1 from telomeres, and the released TRF1 is degraded by the ubiquitin-proteasome pathway. Thus, telomere maintenance by telomerase allows continued proliferation. (B) Oncogenic pathways. Tankyrases are implicated in a number oncogenic pathways, including Wnt, YAP and AKT. (C) Mitosis. Tankyrase 1 has multiple functions in mitosis, including: i) required to resolve sister telomeres during mitosis; ii) localized to mitotic spindle poles during mitosis, where NuMA PARsylation is required for normal spindle formation and iii) regulates CPAP protein stability and function by its PARsylation. (D) DNA repair. Tankyrase 1 stabilizes the NHEJ protein DNA-PK. (E) Apoptosis. Tankyrases are involved in apoptosis, although the mechanism is unclear. TRF1, telomere repeat binding factor 1; PTEN, phosphatase and tensin homolog; YAP, yes-associated protein; AMOT, angiomotins; NuMA, nuclear mitotic apparatus; CPAP, centrosomal P4.1-associated protein; DNA-PK, DNA-dependent protein kinase; NHEJ, non-homologous end joining.