title: Erroneous incorporation of oxidized DNA precursors by Y-family DNA polymerases.
abstract: Deranged oxidative metabolism is a property of many tumour cells. Oxidation of the deoxynucleotide triphosphate (dNTP) pool, as well as DNA, is a major cause of genome instability. Here, we report that two Y-family DNA polymerases of the archaeon Sulfolobus solfataricus strains P1 and P2 incorporate oxidized dNTPs into nascent DNA in an erroneous manner: the polymerases exclusively incorporate 8-OH-dGTP opposite adenine in the template, and incorporate 2-OH-dATP opposite guanine more efficiently than opposite thymine. The rate of extension of the nascent DNA chain following on from these incorporated analogues is only slightly reduced. These DNA polymerases have been shown to bypass a variety of DNA lesions. Thus, our results suggest that the Y-family DNA polymerases promote mutagenesis through the erroneous incorporation of oxidized dNTPs during DNA synthesis, in addition to facilitating translesion DNA synthesis. We also report that human DNA polymerase eta, a human Y-family DNA polymerase, incorporates the oxidized dNTPs in a similar erroneous manner.
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masatomi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Petr
authors.initials: P
authors.lastname: Gruz
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamiya
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Pisani
authors.forename: Chikahide
authors.initials: C
authors.lastname: Masutani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kanke
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
mesh_terms: D019641:DNA, Archaeal / Q000235:genetics* / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003854:Deoxyribonucleotides / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D016944:Sulfolobus / Q000201:enzymology* / Q000235:genetics*
chemical_list: D019641:DNA, Archaeal; D003854:Deoxyribonucleotides; C407743:DNA polymerase mu; D004259:DNA-Directed DNA Polymerase