期刊
JCI INSIGHT
卷 5, 期 18, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.138117
关键词
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资金
- La Ligue Contre le Cancer
- INCa
- Canceropole PACA
- INSERM
- Fondation ARC
- La Ligue Contre le Cancer (Equipe Labellisee)
- Miguel Servet Program from Instituto de Salud Carlos III [CPII13/00017]
- Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III
- European Union (ERDF/ESF, 'Investing in your future') [PI15/00663, PI18/00343]
- Spanish Ministry of Economy and Competitiveness [BFU2016-78232-P, RTI2018-097991-BI00]
- Diputacion General de Aragon (Protein Targets and Bioactive Compounds Group) [E45_17R]
- Diputacion General de Aragon (Digestive Pathology Group) [B25_17R]
- Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd)
- Fondation de France
- China Scholarship Council
- Programme XU GUANGQI
- National Natural Science Foundation of China [81502920]
- Fundamental Research Funds for the Central Universities [106112017CDJQJ468823]
- Agence Nationale de la Recherche [ANR-10-INBS-04-01]
Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1(NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-11S, an organic synthetic molecule, competes with importins for the binding to the NIS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-11S sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-11S reduced SUMOylation of several proteins involved in DNA damage response (DOR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-11S sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.
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