O^6-烷基鸟嘌呤-DNA烷基转移酶基因多态性与肿瘤易感性的关系

Relationship Between Genetic Polymorphisms of Human O^6-Alkylguanine-DNA Alkyltransferase (AGT) Gene and Susceptibility to Tumors

【目的】通过比较表达在中国仓鼠卵巢(CHO)细胞中野生型和突变型O6-烷基鸟嘌呤-DNA烷基转移酶(AGT)对二氯乙基亚硝脲(BCNU)细胞毒性作用的反应差异,探测AGT错译突变体的功能意义。【方法】将野生型及不同突变型AGTcDNA分别转染CHO细胞,选择稳定表达AGT的细胞株,用BCNU作用细胞,以存活细胞簇的数量作为判断细胞毒性标准。【结果】表达AGTLeu84Phe和Leu84Phe/Ile143Val/Lys178Arg突变体的细胞对BCNU的毒性作用抵抗力显著减弱,与此不同的是,其余突变体Ile143Val、Lys178Arg、Ser184Asn以及Ile143Val/Lys178Arg对BCNU毒性作用的抵抗性较野生型AGT无明显差异。【结论】AGTLeu84Phe突变体在修复BCNU造成的DNA损伤过程中酶活性降低。提示AGT基因多态性可能与肿瘤易感性有关。

To determine the functional significance of several missense O6 alkylguanine DNA alkyltransferase (AGT)variants by comparing the toxic response to 1,3 bis (2 chloroethyl) 1 nitrosourea (BCNU)between wild type and variant AGT expressed by Chinese hamster ovary (CHO) cells. Wild type and variant AGT cDNAs were used to transfect the CHO cells. The stable transfectants were then treated with BCNU. Cytotoxicity was determined by the number of surviving colonies.The CHO cells expressing the AGT Leu84Phe and Leu84Phe/ Ile143Val/ Lys178Arg variants were less resistant to BCNU induced cytotoxicity. In contrast, there was no difference in the toxic response to BCNU between wild type AGT and the other AGT variants including Ile143Val, Lys178Arg, Ser184Asn, and le143Val/Lys178Arg. [Conclution]AGT Leu84Phe variant has a reduced activity in repairing BCNU induced DNA damage, indicating that AGT genetic polymorphism may be related to the susceptibility of tumors.