Two Nuclear Localization Signals in USP1 Mediate Nuclear Import of the USP1/UAF1 Complex


Autoria(s): García Santisteban, Iraia; Zorroza, Kerman; Rodríguez Pérez, José Antonio
Data(s)

17/07/2012

17/07/2012

06/06/2012

Resumo

9 p. : il.

The human deubiquitinase USP1 plays important roles in cancer-related processes, such as the DNA damage response, and the maintenance of the undifferentiated state of osteosarcoma cells. USP1 deubiquitinase activity is critically regulated by its interaction with the WD40 repeat-containing protein UAF1. Inhibiting the function of the USP1/UAF1 complex sensitizes cancer cells to chemotherapy, suggesting that this complex is a relevant anticancer target. Intriguingly, whereas UAF1 has been reported to locate in the cytoplasm, USP1 is a nuclear protein, although the sequence motifs that mediate its nuclear import have not been functionally characterized. Here, we identify two nuclear localization signals (NLSs) in USP1 and show that these NLSs mediate the nuclear import of the USP1/UAF1 complex. Using a cellular relocation assay based on these results, we map the UAF1-binding site to a highly conserved 100 amino acid motif in USP1. Our data support a model in which USP1 and UAF1 form a complex in the cytoplasm that subsequently translocates to the nucleus through import mediated by USP1 NLSs. Importantly, our findings have practical implications for the development of USP1-directed therapies. First, the UAF1-interacting region of USP1 identified here might be targeted to disrupt the USP1/UAF1 interaction with therapeutic purposes. On the other hand, we describe a cellular relocation assay that can be easily implemented in a high throughput setting to search for drugs that may dissociate the USP1/UAF1 complex.

Identificador

PLoS ONE 7(6) : (2012) // e38570

1932-6203

http://hdl.handle.net/10810/8377

10.1371/journal.pone.0038570

Idioma(s)

eng

Publicador

Public Library of Science

Relação

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0038570

Direitos

© 2012 Garcia-Santisteban et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

info:eu-repo/semantics/openAccess

Palavras-Chave #Fanconi anemia pathway #ubiquitin system #protein #export #cancer #repair #deubiquitination #identification #sequence #reverse
Tipo

info:eu-repo/semantics/article