title: Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine.
abstract: 8-Oxo-7,8-dihydroguanine (8-oxo-Gua, also known as 8-hydroxyguanine) is a major base lesion that is generated by reactive oxygen species in both the DNA and nucleotide pool. The role of DNA glycosylases, which initiate base excision repair, in the mutagenic processes of 8-oxo-Gua in DNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP, also known as 8-hydroxy-2'-deoxyguanosine 5'-triphosphate) were investigated using supF shuttle plasmids propagated in human cells. The DNA glycosylases, OGG1, MUTYH, NTH1, and NEIL1, in 293T cells were individually knocked-down by siRNAs and plasmid DNAs containing an 8-oxo-Gua:C/8-oxo-Gua:A pair, and 8-oxo-dGTP plus unmodified plasmid DNA were then introduced into the knocked-down cells. The knock-down of OGG1, MUTYH, NTH1, and NEIL1 resulted in a significant increase in G:C-->T:A transversions caused by the 8-oxo-Gua:C pair in the shuttle plasmid. The knock-down of MUTYH resulted in a reduction in A:T-->C:G transversions induced by 8-oxo-dGTP and the 8-oxo-Gua:A pair, but the knockdown of OGG1, NTH1, and NEIL1 had no effect on mutagenesis. These results indicate that all of the above DNA glycosylases suppress mutations caused by 8-oxo-Gua:C in DNA. In contrast, it appears that MUTYH enhances A:T-->C:G mutations caused by 8-oxo-dGTP.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamiya
mesh_terms: D000225:Adenine / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D003848:Deoxyguanine Nucleotides; D034741:RNA, Small Interfering; C078206:8-oxodeoxyguanosine triphosphate; C024829:8-hydroxyguanine; D006147:Guanine; D003596:Cytosine; D004247:DNA; D045647:DNA Glycosylases; D000225:Adenine