Efficient and erroneous incorporation of oxidized DNA precursors by human DNA polymerase eta.
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 report the remarkable nature of human DNA polymerase eta that incorporates oxidized dNTPs into a nascent DNA strand in an efficient and erroneous manner. The polymerase almost exclusively incorporated 8-hydroxy-dGTP (8-OH-dGTP) opposite template adenine (A) at 60% efficiency of normal dTTP incorporation, 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 template A or 2-hydroxy-A paired with template T, G, or C at the termini were efficiently extended. In contrast, human DNA polymerase iota incorporated 8-OH-dGTP opposite template A with much lower efficiency and did not incorporate 2-OH-dATP opposite any of the template bases. It did not extend the primers having the oxidized bases at the termini either. We propose that human DNA polymerase eta may participate in oxidative mutagenesis through the efficient and erroneous incorporation of oxidized dNTPs during DNA synthesis.
Shimizu
Masatomi
M
Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan.
Gruz
Petr
P
Kamiya
Hiroyuki
H
Masutani
Chikahide
C
Xu
Yan
Y
Usui
Yukio
Y
Sugiyama
Hiroshi
H
Harashima
Hideyoshi
H
Hanaoka
Fumio
F
Nohmi
Takehiko
T
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016296:Mutagenesis; D010084:Oxidation-Reduction; D000099270:Y-Family DNA Polymerases
D000255:Adenosine Triphosphate; D004259:DNA-Directed DNA Polymerase; D003848:Deoxyguanine Nucleotides; C095141:2-hydroxydeoxyadenosine triphosphate; C078206:8-oxodeoxyguanosine triphosphate; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases