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  3. A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses

A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses

  • Nat Chem Biol. 2014 Apr;10(4):298-304. doi: 10.1038/nchembio.1455.
Qin Liang 1,  Thomas S Dexheimer 2,  Ping Zhang 1,  Andrew S Rosenthal 2,  Mark A Villamil 1,  Changjun You 3,  Qiuting Zhang 4,  Junjun Chen 1,  Christine A Ott 1,  Hongmao Sun 2,  Diane K Luci 2,  Bifeng Yuan 3,  Anton Simeonov 2,  Ajit Jadhav 2,  Hui Xiao 5,  Yinsheng Wang 3,  David J Maloney 2,  Zhihao Zhuang 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware, USA.
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
  • 3 Department of Chemistry, University of California-Riverside, Riverside, California, USA.
  • 4 State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China.
  • 5 Laboratory of Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York, USA.
PMID: 24531842 DOI: 10.1038/nchembio.1455
Abstract

Protein ubiquitination and deubiquitination are central to the control of a large number of cellular pathways and signaling networks in eukaryotes. Although the essential roles of ubiquitination have been established in the eukaryotic DNA damage response, the deubiquitination process remains poorly defined. Chemical probes that perturb the activity of deubiquitinases (DUBs) are needed to characterize the cellular function of deubiquitination. Here we report ML323 (2), a highly potent inhibitor of the USP1-UAF1 Deubiquitinase complex with excellent selectivity against human DUBs, deSUMOylase, deneddylase and unrelated proteases. Using ML323, we interrogated deubiquitination in the cellular response to UV- and cisplatin-induced DNA damage and revealed new insights into the requirement of deubiquitination in the DNA translesion synthesis and Fanconi anemia pathways. Moreover, ML323 potentiates cisplatin cytotoxicity in non-small cell lung Cancer and osteosarcoma cells. Our findings point to USP1-UAF1 as a key regulator of the DNA damage response and a target for overcoming resistance to the platinum-based Anticancer drugs.

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