DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes.
DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes.
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发表时间：
1996
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通讯作者：
C. W. Lawrence;David C. Hinkle
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作者：
C. W. Lawrence;David C. Hinkle
在跨损伤复制过程中产生的 DNA 损伤诱导的突变可能是许多癌症发展的重要原因。在芽殖酵母（酿酒酵母）中，诱变与 RAD6 修复途径相关，并且取决于 REV1、REV3 和 REV7 基因的功能。酿酒酵母是研究这一过程的良好模型系统。 Rev3和Rev7蛋白是一种新型DNA聚合酶（称为DNA聚合酶zeta）的亚基，它似乎可以进行跨损伤复制，但没有其他修复、重组或复制功能。 Pol zeta 以比酵母 pol α 更高的效率复制经过 T-T 环丁烷二聚体，比该酶更不容易插入不正确的核苷酸，并且在从不匹配的末端延伸方面更有效。 Rev1 蛋白是一种末端核苷酸转移酶，可将 dCMP 插入模板 G、A 和脱碱基位点的对面。跨病灶复制期间诱导的突变类型似乎很大程度上取决于病灶结构，但旁路的频率和准确性也取决于复制条件。 pol zeta 的活性或表达的抑制可能在临床上对接受癌症治疗的患者或具有癌症家族倾向的患者有用。
DNA damage induced mutations arising during the course of translesion replication are likely to be an important contributory cause in the development of many cancers. In budding yeast, Saccharomyces cerevisiae, a good model system with which to investigate this process, mutagenesis is associated with the RAD6 repair pathway and depends on the functions of the REV1, REV3 and REV7 genes. The Rev3 and Rev7 proteins are subunits of a new type of DNA polymerase, called DNA polymerase zeta, that appears to carry out translesion replication, but no other repair, recombination or replication function. Pol zeta replicates past a T-T cyclobutane dimer with a higher efficiency than yeast pol alpha, is less prone than this enzyme to insert an incorrect nucleotide and is more efficient at elongating from a mismatched terminus. Rev1 protein is a terminal nucleotidyl transferase that inserts dCMP opposite template G, A and abasic sites. Types of mutations induced during translesion replication appear to depend largely on lesion structure, but the frequency and accuracy of bypass also depend on replication conditions. Inhibition of the activity or expression of pol zeta may be clinically useful for patients undergoing cancer therapy or for those with a familial predisposition to cancer.