摘要
MGMT作为一种DNA修复蛋白,能够移除DNA上鸟嘌呤O6位点的能致突变毒性和细胞毒性的烷基加合物,从而保护细胞对抗烷化基团的损害,是肿瘤耐受烷化剂药物的主要原因。MGMT在不同的肿瘤和肿瘤细胞系中沉默,MGMT基因启动子CpG岛过甲基化是其表观沉默的主要机制。启动子过甲基化相关的MGMT基因沉默与很多人类肿瘤密切相关。首先,MGMT基因沉默可导致肿瘤相关基因转换突变的累积;其次,MGMT基因过甲基化与肿瘤增强对烷化剂药物敏感性之间呈正相关。这些新发现揭示了MGMT基因甲基化在肿瘤的发生、发展和肿瘤治疗中的重要作用。
O^6-methylguanine DNA methyhransferase （MGMT） was the DNA repair protein responsible for removing mutagenic and cytoxic adducts form O^6-position of guanine in DNA, and plays a crucial role in the defense against alkylating agents. MGMT is silenced in various cancers and cancer lines, and it was believed that the silencing is associated with DNA hypermethylation at the promoter CpG island. This epigenetic silence 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, and it plays a critical role in the development of cancer. Second, there is a strong and significant positive correlation between MGMT promoter hypermethylation and increased tumor sensitivity to alkylating drugs. These finding underline the importance of MGMT promoter hypennethylation in epigenetic mechanisms, carcinogens and clinical implications.
出处
《医学分子生物学杂志》
CAS
CSCD
2008年第4期373-376,共4页
Journal of Medical Molecular Biology
基金
国家自然科学基金(No.30671995)~~
