The telomeric PARP, tankyrases, as targets for cancer therapy - PubMed (original) (raw)

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The telomeric PARP, tankyrases, as targets for cancer therapy

H Seimiya. Br J Cancer. 2006.

Abstract

The requirement for the maintenance of telomeres by telomerase by most cancer cells for continued proliferation is a target in anticancer strategies. Tankyrases are poly(ADP-ribose) polymerases that enhance telomerase access to telomeres. Tankyrase 1 modulates telomerase inhibition in human cancer cells and is reviewed in this report as a potential telomere-directed anticancer target.

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Figures

Figure 1

Structures of tankyrase 1 and tankyrase 2. HPS, homopolymeric runs of His, Pro, and Ser, without known functions; ANK, ankyrin domain, consisting of 24 ANK repeats; SAM, multimerization domain homologous to the sterile alpha motif; PARP, PARP catalytic domain that adds ADP-ribose chains onto acceptor proteins. The ANK domain is further divided into five well-conserved ANK repeat clusters (ARC), each of which contributes to ligand binding. Bridges above two adjacent ANK repeats indicate the presence of a conserved histidine contributing to inter-repeat stabilization.

Figure 2

Telomere elongation by tankyrase 1 and impact on telomerase inhibitors. For telomere elongation, active telomerase needs to gain access to the telomeric 3′-overhang. The TRF1-TIN2-TPP1-POT1 telomeric protein complex limits telomerase access, whereas tankyrase 1 removes the telomeric protein complex by poly(ADP-ribosyl)ating TRF1. Either telomere shortening or tankyrase 1 upregulation, each of which decreases the TRF1-TIN2-TPP1-POT1 loading on a chromosome end, attenuates the impact of telomerase inhibitors by allowing access of residual telomerase activity. Conversely, blockade of tankyrase 1 enhances the effect of telomerase inhibitors. The relative importance of tankyrase 1 vs tankyrase 2 inhibition remains unclear.

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