Chromium(III) decreases the fidelity of human DNA polymerase beta.
Chromium(III) decreases the fidelity of human DNA polymerase beta.
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DOI：
10.1021/bi9731551
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发表时间：
1998-06
期刊：
影响因子：
2.9
通讯作者：
Jatinder Singh;E. T. Snow
中科院分区：
文献类型：
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作者：
Jatinder Singh;E. T. Snow
六价铬的某些颗粒化合物是众所周知的职业和环境人类致癌物。六价铬主要进入细胞并经历代谢还原;然而，铬的最终三价氧化态Cr（III）在细胞内占主导地位。此前已证明DNA结合的Cr（III）会降低M13噬菌体突变试验中复制的保真度。这项研究是为了了解如何铬（III），在生理浓度的镁的存在下，影响稳态DNA合成的动力学参数在体外跨位点特异性O 6-甲基鸟嘌呤（m6 dG）残基的DNA聚合酶β（pol β）。Cr（III）以剂量依赖性方式与短寡聚体模板结合并刺激pol β的活性。Cr（III）刺激相对于m6 dG的dTTP的诱变掺入比dCTP的非诱变掺入更多，并且因此Cr（III）进一步降低通过pol β跨m6 dG的DNA合成的保真度。相比之下，Cr（III）不影响DNA合成在正常模板碱基dG上的保真度。在Cr（III）存在下，增强的活性和诱变损伤旁路可能与Cr（III）依赖性刺激pol β与DNA结合有关，如本文所述。这项研究显示了诱变铬影响DNA合成的一些机制。
Certain particulate compounds of hexavalent chromium are well-known occupational and environmental human carcinogens. Hexavalent chromium primarily enters the cells and undergoes metabolic reduction; however, the ultimate trivalent oxidation state of chromium, Cr(III), predominates within the cell. DNA-bound Cr(III) has been previously shown to decrease the fidelity of replication in the M13 phage mutation assay. This study was done to understand how Cr(III), in the presence of physiological concentrations of magnesium, affects the kinetic parameters of steady-state DNA synthesis in vitro across site-specific O6-methylguanine (m6dG) residues by DNA polymerase beta (pol beta). Cr(III) binds to the short oligomer templates in a dose-dependent manner and stimulates the activity of pol beta. Cr(III) stimulates the mutagenic incorporation of dTTP opposite m6dG more than the nonmutagenic incorporation of dCTP, and thereby Cr(III) further decreases the fidelity of DNA synthesis across m6dG by pol beta. In contrast, Cr(III) does not affect the fidelity of DNA synthesis across the normal template base, dG. Both the enhanced activity and the mutagenic lesion bypass in the presence of Cr(III) may be associated with Cr(III)-dependent stimulation of pol beta binding to DNA as reported here. This study shows some of the mechanisms by which mutagenic chromium affects DNA synthesis.