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首页> 外文期刊>Biochemistry >DNA synthesis past a 5-methylC-containing cis-syn-cyclobutane pyrimidine dimer by yeast pol eta is highly nonmutagenic
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DNA synthesis past a 5-methylC-containing cis-syn-cyclobutane pyrimidine dimer by yeast pol eta is highly nonmutagenic

机译：酵母菌通过一个含5-甲基C的顺式-顺式-环丁烷嘧啶二聚体进行DNA合成是高度不致突变的

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摘要

Cyclobutane pyrimidine dimers (CPDs) are responsible for a considerable fraction of sunlight-induced C to T and 5-methycytosine (C-m) to T mutations in mammalian cells, though the precise mechanism is unknown. One possibility is that the C or C-m of a CPD is not mutagenic and must first deaminate to U or T, respectively, for A to be inserted by a DNA polymerase. Alternatively, A might be directly inserted opposite the C or C-m prior to deamination via an E-imino tautomer of the C or C-m or by a nontemplated mechanism in which the photoproduct is sterically excluded from the active site. We have taken advantage of the retarding effect of C5 methylation on the deamination rate of cis-syn-cyclobutane dimers to prepare a template containing the cis-syn-cyclobutane dimer of mCT. Through the use of single-hit and multiple-hit competition assays, the catalytic core of pol A was found to insert dGMP opposite the C-m of the CPD with about a 120: 1 selectivity relative to dAMP. No significant insertion of dTTP or dCMP was detected. The high fidelity of nonmutagenic insertion opposite the C-m of the CPD provides strong support for the deamination-bypass mechanism for the origin of sunlight induced C -> T mutations.
机译：环丁烷嘧啶二聚体（CPD）导致哺乳动物细胞中相当一部分的阳光诱导的C到T和5-甲基胞嘧啶（C-m）到T突变，尽管确切的机制尚不清楚。一种可能性是CPD的C或C-m不致突变，必须首先脱氨成U或T，才能通过DNA聚合酶插入A。可替代地，在脱氨之前，可以通过C或C-m的E-亚氨基互变异构体或通过非模板机制将A直接插入到C或C-m的对面，其中光产物在空间上从活性位点排除。我们利用C5甲基化对顺式-顺式-环丁烷二聚体的脱氨基速率的阻滞作用来制备包含mCT的顺式-顺式-环丁烷二聚体的模板。通过使用单打击和多打击竞争测定法，发现pol A的催化核心以相对于dAMP约120：1的选择性插入了CPD C-m对面的dGMP。没有检测到明显插入dTTP或dCMP。与CPD的C-m相对的非诱变插入的高保真度为阳光诱导的C-> T突变起源的脱氨旁路机制提供了有力的支持。

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