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ATM regulates 3-Methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents #MMPMID25100205
Agnihotri S; Burrell K; Buczkowicz P; Remke M; Golbourn B; Chornenkyy Y; Gajadhar A; Fernandez NA; Clarke ID; Barszczyk MS; Pajovic S; Ternamian C; Head R; Sabha N; Sobol RW; Taylor MD; Rutka JT; Jones C; Dirks PB; Zadeh G; Hawkins C
Cancer Discov 2014[Oct]; 4 (10): 1198-213 PMID25100205show ga
Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors.