Bugni James M, Han Jiali, Tsai Miaw-sheue, Hunter David J, Samson Leona D
Biological Engineering Division, Biology Department, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
DNA Repair (Amst). 2007 Aug 1;6(8):1116-26. doi: 10.1016/j.dnarep.2007.03.023. Epub 2007 Jun 13.
The DNA repair protein, O(6)-methylguanine DNA-methyltransferase (MGMT) prevents mutations and cell death that result from aberrant alkylation of DNA. The polymorphic variants Leu84Phe, Ile143Val, and Lys178Arg are frequent in the human population. We review here studies of these and other MGMT polymorphisms and their association with risk for lung, breast, colorectal and endometrial cancer with a consideration of gene-environment interactions. In addition, we review studies of the effects of polymorphic variation on alkyltransferase activity and expression. It is formally possible that polymorphic variation could modify functions of MGMT other than its alkyltransferase activity. While it was previously reported that an alkylated form of MGMT modifies Estrogen Receptor alpha activity, from our studies we conclude that this regulation is not a major function of MGMT. Overall, the effects of polymorphic variation on protein function are subtle, and further investigation is required to provide a comprehensive mechanism that explains the observed associations of these variants with risk for cancer.
DNA修复蛋白O(6)-甲基鸟嘌呤DNA甲基转移酶（MGMT）可预防因DNA异常烷基化导致的突变和细胞死亡。亮氨酸84苯丙氨酸、异亮氨酸143缬氨酸和赖氨酸178精氨酸等多态性变体在人群中很常见。我们在此回顾这些以及其他MGMT多态性的研究，及其与肺癌、乳腺癌、结直肠癌和子宫内膜癌风险的关联，并考虑基因-环境相互作用。此外，我们还回顾了多态性变异对烷基转移酶活性和表达影响的研究。从形式上来说，多态性变异可能会改变MGMT除烷基转移酶活性之外的其他功能。虽然此前有报道称MGMT的一种烷基化形式会改变雌激素受体α的活性，但根据我们的研究，我们得出结论，这种调节并非MGMT的主要功能。总体而言，多态性变异对蛋白质功能的影响较为微妙，需要进一步研究以提供一个全面的机制来解释这些变体与癌症风险之间观察到的关联。
