Mutagenic Bypass of 8-Oxo-7,8-dihydroguanine (8-Hydroxyguanine) by DNA Polymerase κ in Human Cells

Kamiya, Hiroyuki; Kurokawa, Masahiro

doi:10.1021/tx300259x

Cited by 19 publications

(25 citation statements)

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“…Oxidative damage in DNA is the first culprit to induce such endogenous DNA lesions. However, 8‐oxoguanine, a typical oxidative DNA damage, is shown to be bypassed by Polk in an error‐prone manner [Jaloszynski et al, ; Vasquez‐Del Carpio et al, ; Kamiya and Kurokawa, ]. Therefore, we speculate that oxidative DNA damage in the guanine base other than 8‐oxoguanine is responsible for the elevation in frequencies of G:C to T:A and G:C to C:G mutations in the liver of aged inactivated Polk KI mice.…”

Section: Discussionmentioning

confidence: 80%

Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene‐induced genotoxicity in vivo

Masumura

Toyoda-Hokaiwado

Niimi

et al. 2017

Environ and Mol Mutagen

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DNA polymerase kappa (Polk) is a specialized DNA polymerase involved in translesion DNA synthesis. To understand the protective roles against genotoxins in vivo, we established inactivated Polk knock-in gpt delta (inactivated Polk KI) mice that possessed reporter genes for mutations and expressed inactive Polk. In this study, we examined genotoxicity of benzo[a]pyrene (BP) to determine whether Polk actually suppressed BP-induced genotoxicity as predicted by biochemistry and in vitro cell culture studies. Seven-week-old inactivated Polk KI and wild-type (WT) mice were treated with BP at doses of 5, 15, or 50 mg/(kg·day) for three consecutive days by intragastric gavage, and mutations in the colon and micronucleus formation in the peripheral blood were examined. Surprisingly, no differences were observed in the frequencies of mutations and micronucleus formation at 5 or 50 mg/kg doses. Inactivated Polk KI mice exhibited approximately two times higher gpt mutant frequency than did WT mice only at the 15 mg/kg dose. The frequency of micronucleus formation was slightly higher in inactivated Polk KI than in WT mice at the same dose, but it was statistically insignificant. The results suggest that Polk has a limited ability to suppress BP-induced genotoxicity in the colon and bone marrow and also that the roles of specialized DNA polymerases in mutagenesis and carcinogenesis should be examined not only by in vitro assays but also by in vivo mouse studies. We also report the spontaneous mutagenesis in inactivated Polk KI mice at young and old ages. Environ. Mol. Mutagen. 58:644-653, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 80%

Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene‐induced genotoxicity in vivo

Masumura

Toyoda-Hokaiwado

Niimi

et al. 2017

Environ and Mol Mutagen

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“…These results indicated that DNA pols η and ζ are involved in error-free bypass of the G O base during the replication of ds DNA (Table 1). In contrast, the G ➔T mutation induced by the oxidized base in the ds shuttle plasmid decreased in the DNA pol κ-knockdown human U2OS cells [28]. This result suggested that DNA pol κ bypasses the G O base in an error-prone manner.…”

Section: Introductionmentioning

confidence: 99%

Mutations induced by 8-hydroxyguanine (8-oxo-7,8-dihydroguanine), a representative oxidized base, in mammalian cells

Suzuki

Kamiya

2016

Genes and Environ

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Guanine oxidation occurs in both DNA and the cellular nucleotide pool, and one of the major products is 8-hydroxyguanine (8-oxo-7,8-dihydroguanine). The mutagenic potentials of this oxidized base have been examined in various experimental systems. In this review, we summarize the mutagenicity of the base in mammalian cells. We also describe the effects of specialized DNA polymerases, DNA repair proteins, and nucleotide pool sanitization enzymes.

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“…pol accurately and efficiently incorporates nucleotides opposite UV-induced cyclobutane pyrimidine dimers (24,25). In addition, pols and are involved in error-prone and errorfree TLS, respectively, of 8-oxo-dG in vivo; pol knockdown reduces G to T transversion mutations caused by 8-oxo-dG in human cells (26), and the absence of pol decreases the accuracy of TLS across 8-oxo-dG in yeast (27).…”

mentioning

confidence: 99%

Impact of Ribonucleotide Backbone on Translesion Synthesis and Repair of 7,8-Dihydro-8-oxoguanine

Sassa

Çağlayan

Rodriguez

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungNumerous ribonucleotides are incorporated into the genome during DNA replication. Oxidized ribonucleotides can also be erroneously incorporated into DNA. Embedded ribonucleotides destabilize the structure of DNA and retard DNA synthesis by DNA polymerases (pols), leading to genomic instability. Mammalian cells possess translesion DNA synthesis (TLS) pols that bypass DNA damage. The mechanism of TLS and repair of oxidized ribonucleotides remains to be elucidated. To address this, we analyzed the miscoding properties of the ribonucleotides riboguanosine (rG) and 7,8-dihydro-8-oxo-riboguanosine (8-oxo-rG) during TLS catalyzed by the human TLS pols and in vitro. The primer extension reaction catalyzed by human replicative pol ␣ was strongly blocked by 8-oxo-rG. pol inefficiently bypassed rG and 8-oxo-rG compared with dG and 7,8-dihydro-8-oxo-2-deoxyguanosine (8-oxo-dG), whereas pol easily bypassed the ribonucleotides. pol ␣ exclusively inserted dAMP opposite 8-oxo-rG. Interestingly, pol preferentially inserted dCMP opposite 8-oxo-rG, whereas the insertion of dAMP was favored opposite 8-oxo-dG. In addition, pol accurately bypassed 8-oxo-rG. Furthermore, we examined the activity of the base excision repair (BER) enzymes 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1 on the substrates, including rG and 8-oxorG. Both BER enzymes were completely inactive against 8-oxo-rG in DNA. However, OGG1 suppressed 8-oxo-rG excision by RNase H2, which is involved in the removal of ribonucleotides from DNA. These results suggest that the different sugar backbones between 8-oxo-rG and 8-oxo-dG alter the capacity of TLS and repair of 8-oxoguanine.

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Mutagenic Bypass of 8-Oxo-7,8-dihydroguanine (8-Hydroxyguanine) by DNA Polymerase κ in Human Cells

Cited by 19 publications

References 50 publications

Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene‐induced genotoxicity in vivo

Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene‐induced genotoxicity in vivo

Mutations induced by 8-hydroxyguanine (8-oxo-7,8-dihydroguanine), a representative oxidized base, in mammalian cells

Impact of Ribonucleotide Backbone on Translesion Synthesis and Repair of 7,8-Dihydro-8-oxoguanine

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