DNA Synthesis Past a 5-MethylC-Containing cis-syn-Cyclobutane Pyrimidine Dimer by Yeast Pol Is Highly Nonmutagenic

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• 作者：Bich Vu ; Vincent J. Cannistraro ; Liping Sun ; John Stephen Taylor
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：August 1, 2006
• 年：2006
• 卷：45
• 期：30
• 页码：9327 - 9335
• 全文大小：355K
• 年卷期：v.45,no.30(August 1, 2006)
• ISSN：1520-4995

文摘

Cyclobutane pyrimidine dimers (CPDs) are responsible for a considerable fraction of sunlight-induced C to T and 5-methycytosine (^mC) to T mutations in mammalian cells, though the precise mechanismis unknown. One possibility is that the C or ^mC of a CPD is not mutagenic and must first deaminate toU or T, respectively, for A to be inserted by a DNA polymerase. Alternatively, A might be directlyinserted opposite the C or ^mC prior to deamination via an E-imino tautomer of the C or ^mC or by anontemplated mechanism in which the photoproduct is sterically excluded from the active site. We havetaken advantage of the retarding effect of C5 methylation on the deamination rate of cis-syn-cyclobutanedimers 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 chars/eta.gif" BORDER=0 > was found to insert dGMP opposite the^mC of the CPD with about a 120:1 selectivity relative to dAMP. No significant insertion of dTTP ordCMP was detected. The high fidelity of nonmutagenic insertion opposite the ^mC of the CPD providesstrong support for the deamination-bypass mechanism for the origin of sunlight induced C T mutations.