Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase.
作者： Yu Zhao , Mona C Majid , Jennifer M Soll , Joshua R Brickner , Sebastian Dango
关键词:
摘要: Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation resistance, which in cancer chemotherapy, depends on the overexpression repair proteins. However, mechanisms responsible this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, a positive regulator ALKBH2 ALKBH3, two demethylases repair. Remarkably, find OTUD4 catalytic activity completely dispensable function. Rather, scaffold USP7 USP9X, deubiquitinases act directly AlkB Moreover, loss USP7, or USP9X tumor cells makes them significantly more sensitive to alkylating agents. Taken together, work reveals novel, noncanonical mechanism by family deubiquitinase regulates its substrates, provides new targets chemotherapy sensitization tumors.
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