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Nucleic Acids Research Advance Access originally published online on October 16, 2007
Nucleic Acids Research 2007 35(21):7140-7149; doi:10.1093/nar/gkm859
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Nucleic Acids Research, 2007, Vol. 35, No. 21 7140-7149
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

3'-Azido-2',3'-dideoxynucleoside 5'-triphosphates inhibit telomerase activity in vitro, and the corresponding nucleosides cause telomere shortening in human HL60 cells

Xiaohong Liu1, Hazuki Takahashi2, Yoko Harada2, Tsukasa Ogawara2, Yuta Ogimura2, Yoshiyuku Mizushina3, Mineo Saneyoshi1,2 and Toyofumi Yamaguchi1,2,*

1Biotechnology Research Center, 2Department of Biosciences, Teikyo University of Science and Technology, Uenohara, Yamanashi 409-0193 and 3Department of Nutritional Science, Laboratory of Food & Nutritional Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan

* To whom correspondence should be addressed. Tel.: +81 554 63 4411; Fax: +81 554 63 4431; Email: toyofumi{at}ntu.ac.jp

Received May 28, 2007. Revised August 6, 2007. Accepted September 27, 2007.

Telomerase adds telomeric DNA repeats to the ends of linear chromosomal DNA. 3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTTP) is a known telomerase inhibitor. To obtain more selective and potent inhibitors that can be employed as tools for studying telomerase, we investigated the telomerase-inhibitory effects of purine nucleosides bearing a 3'-down azido group: 3'-azido-2',3'-dideoxyguanosine (AZddG) 5'-triphosphate (AZddGTP), 3'-azido-2',3'-dideoxy-6-thioguanosine (AZddSG) 5'-triphosphate (AZddSGTP), 3'-azido-2',3'-dideoxyadenosine (AZddA) 5'-triphosphate (AZddATP) and 3'-azido-2',3'-dideoxy-2-aminoadenosine (AZddAA) 5'-triphosphate (AZddAATP). Of these, AZddGTP showed the most potent inhibitory activity against HeLa cell telomerase. AZddGTP was significantly incorporated into the 3'-terminus of DNA by partially purified telomerase. However, AZddGTP did not exhibit significant inhibitory activity against DNA polymerases {alpha} and {delta}, suggesting that AZddGTP is a selective inhibitor of telomerase.

We also investigated whether long-term treatment with these nucleosides could alter telomere length and growth rates of human HL60 cells in culture. Southern hybridization analysis of genomic DNA prepared from cells cultured in the presence of AZddG and AZddAA revealed reproducible telomere shortening.


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