TY - JOUR
T1 - Effects of 8-halo-7-deaza-2′-deoxyguanosine triphosphate on DNA synthesis by DNA polymerases and cell proliferation
AU - Yin, Yizhen
AU - Sasaki, Shigeki
AU - Taniguchi, Yosuke
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Young Scientific (A) (Grant Number 24689006 for Y.T.) and Challenging Exploratory Research (grant number 24659047 for Y.T.) from the Japan Society for the Promotion of Science , and Y.T. acknowledges support from The Uehara Memorial Foundation . Y.Y. was supported by the China Scholarship Council (Grant No. 2011622054 ). This research is partially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from Japan Agency for Medical Research and Development (AMED).
PY - 2016
Y1 - 2016
N2 - 8-OxodG (8-oxo-2′-deoxyguanosine) is representative of nucleoside damage and shows a genotoxicity. To significantly reveal the contributions of 7-NH and C8-oxygen to the mutagenic effect of 8-oxodG by DNA polymerases, we evaluated the effects of the 8-halo-7-deaza-dG (8-halogenated 7-deaza-2′-deoxyguanosine) derivatives by DNA polymerases. 8-Halo-7-deaza-dGTPs were poorly incorporated by both KF(exo−) and human DNA polymerase β opposite dC or dA into the template DNA. Furthermore, it was found that KF(exo−) was very sensitive to the introduction of the C8-halogen, while polymerase β can accommodate the C8-halogen resulting in an efficient dCTP insertion opposite the 8-halo-7-deaza-dG in the template DNA. These results indicate that strong hydrogen bonding between 7-NH in the 8-oxo-G nucleobase and 1-N in the adenine at the active site of the DNA polymerase is required for the mutagenic effects. Whereas, I-deaza-dGTP shows an antiproliferative effect for the HeLa cells, suggesting that it could become a candidate as a new antitumor agent.
AB - 8-OxodG (8-oxo-2′-deoxyguanosine) is representative of nucleoside damage and shows a genotoxicity. To significantly reveal the contributions of 7-NH and C8-oxygen to the mutagenic effect of 8-oxodG by DNA polymerases, we evaluated the effects of the 8-halo-7-deaza-dG (8-halogenated 7-deaza-2′-deoxyguanosine) derivatives by DNA polymerases. 8-Halo-7-deaza-dGTPs were poorly incorporated by both KF(exo−) and human DNA polymerase β opposite dC or dA into the template DNA. Furthermore, it was found that KF(exo−) was very sensitive to the introduction of the C8-halogen, while polymerase β can accommodate the C8-halogen resulting in an efficient dCTP insertion opposite the 8-halo-7-deaza-dG in the template DNA. These results indicate that strong hydrogen bonding between 7-NH in the 8-oxo-G nucleobase and 1-N in the adenine at the active site of the DNA polymerase is required for the mutagenic effects. Whereas, I-deaza-dGTP shows an antiproliferative effect for the HeLa cells, suggesting that it could become a candidate as a new antitumor agent.
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U2 - 10.1016/j.bmc.2016.06.030
DO - 10.1016/j.bmc.2016.06.030
M3 - Article
C2 - 27372838
AN - SCOPUS:84977659728
VL - 24
SP - 3856
EP - 3861
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 16
ER -