Duckett D R, Drummond J T, Murchie A I, Reardon J T, Sancar A, Lilley D M, Modrich P
Howard Hughes Medical Institute and Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6443-7. doi: 10.1073/pnas.93.13.6443.
Bacterial and mammalian mismatch repair systems have been implicated in the cellular response to certain types of DNA damage, and genetic defects in this pathway are known to confer resistance to the cytotoxic effects of DNA-methylating agents. Such observations suggest that in addition to their ability to recognize DNA base-pairing errors, members of the MutS family may also respond to genetic lesions produced by DNA damage. We show that the human mismatch recognition activity MutSalpha recognizes several types of DNA lesion including the 1,2-intrastrand d(GpG) crosslink produced by cis-diamminedichloroplatinum(II), as well as base pairs between O6-methylguanine and thymine or cytosine, or between O4-methylthymine and adenine. However, the protein fails to recognize 1,3-intrastrand adduct produced by trans-diamminedichloroplatinum(II) at a d(GpTpG) sequence. These observations imply direct involvement of the mismatch repair system in the cytotoxic effects of DNA-methylating agents and suggest that recognition of 1,2-intrastrand cis-diamminedichloroplatinum(II) adducts by MutSalpha may be involved in the cytotoxic action of this chemotherapeutic agent.
细菌和哺乳动物的错配修复系统与细胞对某些类型DNA损伤的反应有关，已知该途径中的遗传缺陷会赋予对DNA甲基化剂细胞毒性作用的抗性。这些观察结果表明，除了识别DNA碱基配对错误的能力外，MutS家族成员可能还对DNA损伤产生的遗传损伤有反应。我们发现人类错配识别活性蛋白MutSα能识别几种类型的DNA损伤，包括顺式二氯二氨合铂（II）产生的1,2-链内d（GpG）交联，以及O6-甲基鸟嘌呤与胸腺嘧啶或胞嘧啶之间，或O4-甲基胸腺嘧啶与腺嘌呤之间的碱基对。然而，该蛋白无法识别反式二氯二氨合铂（II）在d（GpTpG）序列处产生的1,3-链内加合物。这些观察结果意味着错配修复系统直接参与了DNA甲基化剂的细胞毒性作用，并表明MutSα对1,2-链内顺式二氯二氨合铂（II）加合物的识别可能参与了这种化疗药物的细胞毒性作用。
