The efficiency and fidelity of 8-oxo-guanine bypass by DNA polymerases δ and η
The efficiency and fidelity of 8-oxo-guanine bypass by DNA polymerases δ and η
复制标题
DNA 聚合酶 δ 和 η 绕过 8-氧代鸟嘌呤的效率和保真度
作者：
S. McCulloch;R. Kokoska;Parie Garg;P. Burgers;T. Kunkel
氧化应激造成的DNA损伤是7,8-二氢-8-氧鸟嘌呤（8-oxoG）。由于8-oxoG在DNA合成过程中可能与腺嘌呤错配，因此了解DNA聚合酶绕过8-oxoG的效率和保真度是很有意义的。我们量化了涉及8-oxoG旁路的两种DNA聚合酶的旁路参数，Pols δ和η。酵母菌Pol δ和Pol η均旁路8-oxoG，并在旁路过程中错溶腺嘌呤。然而，酵母Pol η的效率是Pol δ的10倍，并且在旁路后Pol η切换到较少的过程合成，类似于在顺式syn胸腺嘧啶-胸腺嘧啶二聚体旁路时观察到的情况。此外，在8-oxoG旁路过程中，酵母Pol η的准确度至少是酵母Pol δ的10倍。在辅助蛋白RFC、PCNA和RPA存在的情况下，这些差异得以维持，这与Pol η在抑制ogg1依赖性突变中的作用一致。人类和小鼠的Pol η得到了惊人的不同结果。这两种哺乳动物酶都能有效地绕过8-oxoG，但它们的过程性较差，没有开关点，保真度远低于酵母Pol η。事实上，酵母和哺乳动物Pol η具有本质上不同的催化性质，具有潜在的生物学意义。
A DNA lesion created by oxidative stress is 7,8-dihydro-8-oxo-guanine (8-oxoG). Because 8-oxoG can mispair with adenine during DNA synthesis, it is of interest to understand the efficiency and fidelity of 8-oxoG bypass by DNA polymerases. We quantify bypass parameters for two DNA polymerases implicated in 8-oxoG bypass, Pols δ and η. Yeast Pol δ and yeast Pol η both bypass 8-oxoG and misincorporate adenine during bypass. However, yeast Pol η is 10-fold more efficient than Pol δ, and following bypass Pol η switches to less processive synthesis, similar to that observed during bypass of a cis-syn thymine-thymine dimer. Moreover, yeast Pol η is at least 10-fold more accurate than yeast Pol δ during 8-oxoG bypass. These differences are maintained in the presence of the accessory proteins RFC, PCNA and RPA and are consistent with the established role of Pol η in suppressing ogg1-dependent mutagenesis in yeast. Surprisingly different results are obtained with human and mouse Pol η. Both mammalian enzymes bypass 8-oxoG efficiently, but they do so less processively, without a switch point and with much lower fidelity than yeast Pol η. The fact that yeast and mammalian Pol η have intrinsically different catalytic properties has potential biological implications.
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DOI：
10.1073/pnas.0505949102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Garg, P;Burgers, PM
通讯作者：
Burgers, PM
影响因子：
14.9
作者：
Yanbin Zhang;F. Yuan;Xiaohua Wu;O. Rechkoblit;John-Stephen A Taylor;N. Geacintov;Zhigang Wang
通讯作者：
Yanbin Zhang;F. Yuan;Xiaohua Wu;O. Rechkoblit;John-Stephen A Taylor;N. Geacintov;Zhigang Wang
影响因子：
3.3
作者：
Deem, Angela;Barker, Krista;Malkova, Anna
通讯作者：
Malkova, Anna
影响因子：
11.2
作者：
Lin, QC;Clark, AB;Kucherlapati, R
通讯作者：
Kucherlapati, R
DOI：
10.1073/pnas.92.3.719
发表时间：
1995-01-31
影响因子：
11.1
作者：
LIPSCOMB, LA;PEEK, ME;WILLIAMS, LD
通讯作者：
WILLIAMS, LD