Mitochondrial Targeting of Human O6-Methylguanine DNA Methyltransferase Protects against Cell Killing by Chemotherapeutic Alkylating Agents

摘要: DNA repair capacity of eukaryotic cells has been studied extensively in recent years. Mammalian have engineered to overexpress recombinant nuclear proteins from ectopic genes assess the impact increased on genome stability. This approach used this study specifically target O(6)-methylguanine methyltransferase (MGMT) mitochondria and examine its cell survival after exposure alkylating agents. Survival human hematopoietic lines primary CD34(+) committed progenitor was monitored because baseline for alkylation-induced damage is typically low due insufficient expression MGMT. Increased observed when K562 were transfected with nuclear-targeted MGMT (nucl-MGMT) or mitochondrial-targeted (mito-MGMT). Furthermore, overexpression mito-MGMT provided greater resistance killing by 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) than nucl-MGMT. Simultaneous nucl-MGMT did not enhance alone. Overexpression either also conferred a similar level methyl methanesulfonate (MMS) temozolomide (TMZ) but simultaneous both cellular compartments neither additive nor synergistic. When infected oncoretroviral vectors that targeted O(6)-benzylguanine (6BG)-resistant (MGMT(P140K)) nucleus mitochondria, progenitors derived resistant 6BG/BCNU 6BG/TMZ. These studies indicate mitochondrial targeting protects against BCNU, TMZ, MMS, which consistent possibility contribute equally agent-induced during chemotherapy.