A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses.
Nat Chem Biol
; 10(4): 298-304, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24531842
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Proteínas Nucleares
/
Proteínas de Arabidopsis
/
Ubiquitinação
/
Proteases Específicas de Ubiquitina
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos