A Redox Role for the [4Fe4S] Cluster of Yeast DNA Polymerase δ

被引:35
作者
Bartels, Phillip L. [1 ]
Stodola, Joseph L. [2 ]
Burgers, Peter M. J. [2 ]
Barton, Jacqueline K. [1 ]
机构
[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
[2] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA
基金
美国国家科学基金会;
关键词
IRON-SULFUR CLUSTER; CHARGE-TRANSPORT; 4FE-4S CLUSTERS; REPLICATION FORKS; REPAIR PROTEINS; HUMAN-CELLS; DUPLEX DNA; DELTA; ELECTROCHEMISTRY; FERREDOXIN;
D O I
10.1021/jacs.7b10284
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A [4Fe4S](2+) cluster in the C-terminal domain of the catalytic subunit of the eukaryotic B-family DNA polymerases is essential for the formation of active multi-subunit complexes. Here we use a combination of electrochemical and biochemical methods to assess the redox activity of the [4Fe4S](2+) cluster in Saccharomyces cerevisiae polymerase (Pol) delta, the lagging strand DNA polymerase. We find that Pol delta bound to DNA is indeed redox-active at physiological potentials, generating a DNA-mediated signal electrochemically with a midpoint potential of 113 +/- 5 mV versus NHE. Moreover, biochemical assays following electrochemical oxidation of Pol delta reveal a significant slowing of DNA synthesis that can be fully reversed by reduction of the oxidized form. A similar result is apparent with photooxidation using a DNA-tethered anthraquinone. These results demonstrate that the [4Fe4S] cluster in Pol delta can act as a redox switch for activity, and we propose that this switch can provide a rapid and reversible way to respond to replication stress.
引用
收藏
页码:18339 / 18348
页数:10
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