Journal
EMBO JOURNAL
Volume 34, Issue 12, Pages 1687-1703Publisher
WILEY-BLACKWELL
DOI: 10.15252/embj.201490497
Keywords
AlkB; alkylation/OTUD4; deubiquitinase; DNA repair
Categories
Funding
- Cell and Molecular Biology Training Grant [5T32GM007067-40]
- NIH [K08 CA158133, R01 CA193318]
- American Cancer Society [IRG-58-010-56]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available