A Selective USP1-UAF1 Inhibitor Links Deubiquitination to DNA Damage Responses

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2014 Feb 18

PMID 24531842

Citations 139

Authors

Qin Liang

Thomas S Dexheimer

Ping Zhang

Andrew S Rosenthal

Mark A Villamil

Changjun You

Qiuting Zhang

Junjun Chen

Christine A Ott

Hongmao Sun

Diane K Luci

Bifeng Yuan

Anton Simeonov

Ajit Jadhav

Hui Xiao

Yinsheng Wang

David J Maloney

Zhihao Zhuang

Affiliations

Soon will be listed here.

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.

Citing Articles

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