Single-turnover kinetic analysis of the mutagenic potential of 8-oxo-7,8-dihydro-2′-deoxyguanosine during gap-filling synthesis catalyzed by human DNA polymerases λ and β

被引:57
|
作者
Brown, Jessica A.
Duym, Wade W.
Fowler, Jason D.
Suo, Zucai [1 ]
机构
[1] Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA
[2] Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA
[3] Ohio State Univ, Ohio State Biophys Program, Columbus, OH 43210 USA
[4] Ohio State Univ, Mol Cellular & Dev Biol Program, Columbus, OH 43210 USA
[5] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
关键词
single-turnover kinetics; 8-oxodG; base excision repair; DNA polymerase lambda; DNA polymerase beta; BASE-EXCISION-REPAIR; STEADY-STATE; NUCLEOTIDE INSERTION; OXIDATIVE DAMAGE; STRUCTURAL BASIS; NICKED DNA; POL LAMBDA; FIDELITY; 7,8-DIHYDRO-8-OXOGUANINE; EFFICIENT;
D O I
10.1016/j.jmb.2007.01.069
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) damage, many DNA polymerases exhibit a dual coding potential which facilitates efficient incorporation of matched dCTP or mismatched dATP This also holds true for the insertion of 8-oxodGTP opposite template bases dC and dA. Employing single-turnover kinetic methods, we examined human DNA polymerase beta and its novel X-family homolog, human DNA polymerase lambda, to determine which nucleotide and template base was preferred when encountering 8-oxodG and 8-oxodGTP, respectively. While DNA polymerase beta preferentially incorporated dCTP over dATP, DNA polymerase lambda did not modulate a preference for either dCTP or dATP when opposite 8-oxodG in single-nucleotide gapped DNA, as incorporation proceeded with essentially equal efficiency and probability. Moreover, DNA polymerase lambda is more efficient than DNA polymerase beta to fill this oxidized single-nucleotide gap.. Insertion of 8-oxodGTP by both DNA polymerases lambda and beta occurred predominantly against template dA, thereby reiterating how the asymmetrical design of the polymerase active site differentially accommodated the anti and syn conformations of 8-oxodG and 8-oxodGTP. Although the electronegative oxygen at the C8 position of 8-oxodG may induce DNA structural perturbations, human DNA ligase I was found to effectively ligate the incorporated 8-oxodGMP to a downstream strand, which sealed the nicked DNA. Consequently, the erroneous nucleotide incorporations catalyzed by DNA polymerases lambda and beta as well as the subsequent ligation catalyzed by a DNA ligase during base excision repair are a threat to genomic integrity. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1258 / 1269
页数:12
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