Jacinto Filipe V, Esteller Manel
Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
DNA Repair (Amst). 2007 Aug 1;6(8):1155-60. doi: 10.1016/j.dnarep.2007.03.013. Epub 2007 May 7.
Alkylation of DNA at the O(6)-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. O(6)-alkylguanine-DNA alkyltransferase (AGT), also known as O(6)-methylguanine-DNA methyltransferase (MGMT), is the DNA repair protein responsible for removing alkylation adducts from the O(6)-position of guanine in DNA. The promoter CpG island hypermethylation-associated gene silencing of MGMT is associated with a wide spectrum of human tumors. This epigenetic inactivation of MGMT has two main consequences in human cancer. First, it uncovers a new mutator pathway that causes the accumulation of G-to-A transition mutations that can affect genes required for genomic stability. Second, there is a strong and significant positive correlation between MGMT promoter hypermethylation and increased tumor sensitivity to alkylating drugs. These findings underline the importance of MGMT promoter hypermethylation in basic and translational cancer research.
鸟嘌呤O(6)位的DNA烷基化是导致突变、癌症和细胞死亡的最关键事件之一。O(6)-烷基鸟嘌呤-DNA烷基转移酶（AGT），也称为O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT），是负责从DNA中鸟嘌呤的O(6)位去除烷基化加合物的DNA修复蛋白。MGMT启动子CpG岛高甲基化相关的基因沉默与多种人类肿瘤有关。MGMT的这种表观遗传失活在人类癌症中有两个主要后果。首先，它揭示了一种新的诱变途径，该途径导致G-to-A转换突变的积累，这些突变可能影响基因组稳定性所需的基因。其次，MGMT启动子高甲基化与肿瘤对烷化剂药物敏感性增加之间存在强烈且显著的正相关。这些发现强调了MGMT启动子高甲基化在基础和转化癌症研究中的重要性。
