Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase

Yu Zhao, Mona C. Majid, Jennifer M. Soll, Joshua R. Brickner, Sebastian Dango, Nima Mosammaparast

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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

Original languageEnglish
Pages (from-to)1687-1703
Number of pages17
JournalEMBO Journal
Issue number12
StatePublished - Jun 12 2015


  • AlkB
  • Alkylation/OTUD4
  • DNA repair
  • Deubiquitinase


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