期刊
DNA REPAIR
卷 1, 期 7, 页码 559-569出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S1568-7864(02)00055-1
关键词
lesion bypass; translesion synthesis; polymerase kappa; mutagenesis; benzo[a]pyrene; DNA adducts
资金
- NCI NIH HHS [CA92768, CA20851] Funding Source: Medline
In cells, the major benzo[a]pyrene DNA adduct is the highly mutagenic (+)-trans-anti-BPDE-N-2-dG. In eukaryotes, little is known about lesion bypass of this DNA adduct during replication. Here, we show that purified human Polkappa can effectively bypass a template (+)-trans-anti-BPDE-N-2-dG adduct in an error-free manner. Kinetic parameters indicate that Polkappa bypass of the (-)-trans-anti-BPDE-N-2-dG adduct was similar to41-fold more efficient compared to the (+)-trans-anti-BPDE-N-2-dG adduct. Furthermore, we have found another activity of human Polkappa in response to the (+)- and (-)-trans-anti-BPDE-N-2-dG adducts: extension synthesis from mispaired primer 3' ends opposite the lesion. In contrast, the two adducts strongly blocked DNA synthesis by the purified human Polbeta and the purified catalytic subunits of yeast Polalpha, Poldelta, and Polepsilon right before the lesion. Extension by human Polkappa from the primer 3'G opposite the (+)- and (-)-trans-anti-BPDE-N-2-dG adducts was mediated by a -1 deletion mechanism, probably resulting from re-aligning the primer G to pair with the next template C by Polkappa prior to DNA synthesis. Thus, sequence contexts 5' to the lesion strongly affect the fidelity and mechanism of the Polkappa-catalyzed extension synthesis. These results support a dual-function model of human Polkappa in bypass of BPDE DNA adducts: it may function both as an error-free bypass polymerase alone and an extension synthesis polymerase in combination with another polymerase. (C) 2002 Elsevier Science B.V. All rights reserved.
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