文章：

MGMT：它在癌症病因学和癌症治疗中的作用

MGMT: its role in cancer aetiology and cancer therapeutics

原文发布日期：2004-04-01

DOI: 10.1038/nrc1319

类型: Review Article

开放获取: 否

要点：

1. The DNA-repair protein O⁶-alkylguanine-DNA-alkyltransferase (AGT) is encoded by the gene O⁶-methylguanine-DNA-methyltransferase (MGMT).
2. AGT removes alkylating lesions at position O6 of guanine and therefore has an important role in maintaining normal cell physiology and genomic stability.
3. A broad range of expression of AGT is noted across tumours and normal tissues. Its expression also helps to prevent carcinogenesis and is a target for chemotherapy.
4. Overexpression of MGMT reduces the risk of carcinogenesis and the risk of mutations after exposure to methylating agents.
5. Loss of MGMT is associated with increased carcinogenic risk and increased sensitivity to methylating agents.
6. MGMT-promoter methylation shuts off MGMT expression in tumours and increases responsiveness to chemotherapy.
7. O⁶-benzylguanine is a specific inhibitor of AGT, but mutations in the active-site pocket of the protein can cause resistance to the drug.
8. MGMT genes with such mutations are effective for use in gene therapy for transducing drug resistance into haematopoietic stem cells, to protect these cells from the toxic effects of chemotherapy.
9. The physiological role of MGMT remains an area of active investigation.

要点翻译：

1. DNA修复蛋白O6-烷基鸟嘌呤-DNA-烷基转移酶（AGT）由O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）基因编码。
2. AGT可清除鸟嘌呤O6位点的烷基化损伤，因此在维持正常细胞生理功能和基因组稳定性方面具有重要作用。
3. 肿瘤组织和正常组织中均存在广泛的AGT表达差异。该蛋白的表达不仅有助于预防癌变，也是化学疗法的靶向目标。
4. MGMT的过度表达可降低致癌风险以及接触甲基化试剂后的突变风险。
5. MGMT基因缺失则会增加致癌风险和对甲基化试剂的敏感性。
6. MGMT启动子甲基化会关闭肿瘤中的MGMT表达，从而增强对化疗的敏感性。
7. O6-苄基鸟嘌呤是AGT的特异性抑制剂，但该蛋白活性位点口袋的突变可能导致耐药性。
8. 携带此类突变的MGMT基因可用于基因治疗，将耐药性转导至造血干细胞，从而保护这些细胞免受化疗的毒性影响。
9. MGMT的生理功能仍是当前活跃的研究领域。

英文摘要：

The DNA-repair protein O6-alkylguanine DNA alkyltransferase (AGT) has a wide range of activity in normal tissues and its evolutionary conservation indicates a fundamental role in cell physiology and maintenance of the genome. Through removal of alkylating lesions at O6 of guanine, AGT protects against mutagenesis and malignant transformation. In tumours, AGT provides resistance to treatment with alkylating agents, unless expression is lost by methylation of the promoter of the gene encoding AGT — O6-methylguanine-DNA-methyltransferase (MGMT) — or there is direct inhibition of AGT activity. When overexpressed in stem cells, MGMT serves as a drug-selection gene for gene therapy and protects normal tissues from the toxic effects of chemotherapy.

摘要翻译： 

DNA修复蛋白O6-烷基鸟嘌呤DNA烷基转移酶（AGT）在正常组织中具有广泛的活性，其在进化过程中的保守性表明它在细胞生理和基因组维持中扮演基础角色。通过去除鸟嘌呤O6位上的烷基化损伤，AGT可防止突变和恶性转化。在肿瘤中，AGT可介导对烷化剂治疗的耐药性，除非编码AGT的基因——O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）——的启动子发生甲基化导致其表达丧失，或AGT活性被直接抑制。当在干细胞中过表达时，MGMT可作为基因治疗的药物筛选基因，并保护正常组织免受化疗毒性影响。

原文链接：

MGMT: its role in cancer aetiology and cancer therapeutics