Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.
Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China; Department of Medical Technology, Beijing Pharmaceutical University of Staff and Workers, Beijing 100079, China.
DNA Repair (Amst). 2023 Mar;123:103449. doi: 10.1016/j.dnarep.2023.103449. Epub 2023 Jan 14.
Alkylating agents are genotoxic chemicals that can induce and treat various types of cancer. This occurs through covalent bonding with cellular macromolecules, in particular DNA, leading to the loss of functional integrity under the persistence of modifications upon replication. O-alkylguanine (O-AlkylG) adducts are proposed to be the most potent DNA lesions induced by alkylating agents. If not repaired correctly, these adducts can result, at the molecular level, in DNA point mutations, chromosome aberrations, recombination, crosslinking, and single- and double-strand breaks (SSB/DSBs). At the cellular level, these lesions can result in malignant transformation, senescence, or cell death. O-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein capable of removing the alkyl groups from O-AlkylG adducts in a damage reversal process that can prevent the adverse biological effects of DNA damage caused by guanine O-alkylation. MGMT can thereby defend normal cells against tumor initiation, however it can also protect tumor cells against the beneficial effects of chemotherapy. Hence, MGMT can play an important role in both the prevention and treatment of cancer; thus, it can be considered as a double-edged sword. From a clinical perspective, MGMT is a therapeutic target, and it is important to explore the rational development of its clinical exploitation.
烷化剂是一种遗传毒性化学物质，可以诱导和治疗多种类型的癌症。这是通过与细胞大分子，特别是 DNA 的共价键合来实现的，导致在复制过程中修饰物持续存在的情况下，功能完整性丧失。O-烷基鸟嘌呤（O-AlkylG）加合物被认为是烷化剂诱导的最有效的 DNA 损伤。如果不正确修复，这些加合物可能会导致分子水平上的 DNA 点突变、染色体畸变、重组、交联以及单链和双链断裂（SSB/DSBs）。在细胞水平上，这些损伤可导致恶性转化、衰老或细胞死亡。O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）是一种 DNA 修复蛋白，能够在损伤逆转过程中从 O-AlkylG 加合物中去除烷基，从而防止鸟嘌呤 O-烷基化引起的 DNA 损伤的不良生物学效应。MGMT 可以保护正常细胞免受肿瘤起始的影响，但也可以保护肿瘤细胞免受化疗的有益影响。因此，MGMT 在癌症的预防和治疗中都起着重要的作用；因此，它可以被视为一把双刃剑。从临床角度来看，MGMT 是一个治疗靶点，探索其临床开发的合理性非常重要。
