Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers

甲基转移酶 DNA修复 O-6-甲基鸟嘌呤-DNA甲基转移酶 相扑蛋白 DNA损伤 二硫仑 癌症研究 DNA甲基转移酶 DNA 生物 化学 生物化学 泛素 甲基化 基因
作者
Kalkunte S. Srivenugopal,Amit Rawat,Suryakant K. Niture,Ameya Paranjpe,Chinavenmani S. Velu,Sanjay N. Venugopal,Hanumantha Rao Madala,Debasish Basak,Surendra R. Punganuru
出处
期刊:Mini-reviews in Medicinal Chemistry [Bentham Science]
卷期号:16 (6): 455-464 被引量:18
标识
DOI:10.2174/1389557515666150722101046
摘要

O6-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O6-alkylguanine adducts, including those generated by the clinically used anticancer alkylating agents, it has emerged as a central and rational target for overcoming tumor resistance to alkylating agents. Although the pseudosubstrates for MGMT [O6-benzylguanine, O6-(4- bromothenyl)guanine] have gained attention as powerful and clinically-relevant inhibitors, bone marrow suppression due to excessive alkylation damage has diminished this strategy. Our laboratory has been working on various posttranslational modifications of MGMT that affect its protein stability, DNA repair activity and response to oxidative stress. While these modifications greatly impact the physiological regulation of MGMT, they also highlight the opportunities for inactivating DNA repair and new drug discovery in this specific area. This review briefly describes the newer aspects of MGMT posttranslational regulation by ubiquitination, sumoylation and glutathionylation and reveals how the reactivity of the active site Cys145 can be exploited for potent inhibition and depletion of MGMT by thiol-reacting drugs such as the disulfiram and various dithiocarbamate derivatives. The possible repurposing of these nontoxic and safe drugs for improved therapy of pediatric and adult brain tumors is discussed. Keywords: Alkylating agents, DNA repair, Drug repurposing, gliomas, Protein glutathionylation, Reactive cysteines.
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