Synthetic Nucleosides and Nucleotides. 43. Inhibition of Vertebrate Telomerases by Carbocyclic Oxetanocin G (C.OXT-G) Triphosphate Analogues and Influence of C.OXT-G Treatment on Telomere Length in Human HL60 Cells

Telomerase, responsible for telomere synthesis, is expressed in ∼ 90% of human tumor cells but seldom in normal somatic cells. In this study, inhibition by carbocyclic oxetanocin G triphosphate (C.OXT-GTP) and its analogues was investigated in order to clarify the susceptibility of telomerase to various nucleotide analogues. C.OXT-GTP competitively inhibited telomerase activity with respect to dGTP. However, C.OXT-GTP had a potent inhibitory effect on DNA polymerase α. It was examined whether the nucleoside (C.OXT-G) was able to alter telomere length in cultured human HL60 cells. Contrary to expectation, long-term treatment with 10 μM C.OXT-G was found to cause telomere lengthening.

Keywords:

• Carbocyclic oxetanocin
• DNA polymerase
• Telomerase
• Telomere lengthening
• Telomere shortening

Acknowledgments

We thank Dr. Teruo Azuma, Nikkou Branch Institute, National Research Institute of Fisheries Science, Fisheries Research Agency, for kindly providing immature male cherry salmon. This work was supported in part by the High-Technology Research Center Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

This article is dedicated to Professor Eiko Ohtsuka on the occasion of her 70th birthday.

Part 42 of this series: Yamaguchi, T., Yamada, R., Tomikawa, A., Shudo, K., Saito, M., Ishikawa, F., and Saneyoshi, M. 2000. Biochem. Biophys. Res. Commun. 279, 475–481.