Efficient and Erroneous Incorporation of Oxidized DNA Precursors by Human DNA Polymerase
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- 作者：Masatomi Shimizu ; Petr Gruz ; Hiroyuki Kamiya ; Chikahide Masutani ; Yan Xu ; Yukio Usui ; Hiroshi Sugiyama ; Hideyoshi Harashima ; Fumio Hanaoka ; Takehiko Nohmi
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：May 8, 2007
- 年：2007
- 卷：46
- 期：18
- 页码：5515 - 5522
- 全文大小：188K
- 年卷期：v.46,no.18(May 8, 2007)
- ISSN：1520-4995
文摘
Altered oxidative metabolism is a property of many tumor cells. Oxidation of DNA precursors,i.e., dNTP pool, as well as DNA is a major source of mutagenesis and carcinogenesis. Here, we reportthe remarkable nature of human DNA polymerase 
that incorporates oxidized dNTPs into a nascentDNA strand in an efficient and erroneous manner. The polymerase almost exclusively incorporated8-hydroxy-dGTP (8-OH-dGTP) opposite template adenine (A) at 60% efficiency of normal dTTPincorporation, and incorporated 2-hydroxy-dATP (2-OH-dATP) opposite template thymine (T), guanine(G), or cytosine (C) at substantial rates. The synthetic primers having 8-hydroxy-G paired with templateA or 2-hydroxy-A paired with template T, G, or C at the termini were efficiently extended. In contrast,human DNA polymerase 
incorporated 8-OH-dGTP opposite template A with much lower efficiencyand did not incorporate 2-OH-dATP opposite any of the template bases. It did not extend the primershaving the oxidized bases at the termini either. We propose that human DNA polymerase may participatein oxidative mutagenesis through the efficient and erroneous incorporation of oxidized dNTPs duringDNA synthesis.
that incorporates oxidized dNTPs into a nascentDNA strand in an efficient and erroneous manner. The polymerase almost exclusively incorporated8-hydroxy-dGTP (8-OH-dGTP) opposite template adenine (A) at 60% efficiency of normal dTTPincorporation, and incorporated 2-hydroxy-dATP (2-OH-dATP) opposite template thymine (T), guanine(G), or cytosine (C) at substantial rates. The synthetic primers having 8-hydroxy-G paired with templateA or 2-hydroxy-A paired with template T, G, or C at the termini were efficiently extended. In contrast,human DNA polymerase incorporated 8-OH-dGTP opposite template A with much lower efficiencyand did not incorporate 2-OH-dATP opposite any of the template bases. It did not extend the primershaving the oxidized bases at the termini either. We propose that human DNA polymerase may participatein oxidative mutagenesis through the efficient and erroneous incorporation of oxidized dNTPs duringDNA synthesis.