HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response

• Published in: Scientific reports 2015-08, Vol.5 (1), p.12793-12793, Article 12793
• Main Authors: Lim, Key-Hwan, Park, Jang-Joon, Gu, Bon-Hee, Kim, Jin-Ock, Park, Sang Gyu, Baek, Kwang-Hyun
• Format: Article
• Language: English
• Subjects: 631/67/395; 631/67/70; 82/29; 82/47; 82/58; 96/2; 96/95; Annexin A1 - genetics; Annexin A1 - metabolism; Binding sites; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Gene Expression Regulation; HCT116 Cells; HEK293 Cells; HeLa Cells; Herpes viruses; Humanities and Social Sciences; Humans; Irradiation; MCF-7 Cells; MDM2 protein; multidisciplinary; Nucleolin; p53 Protein; Peptides; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Stability; Proteinase; Proteolysis; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Radiation; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Signal Transduction; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-protein ligase; Ubiquitin-Specific Peptidase 7; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep12793

HAUSP (herpes virus-associated ubiquitin specific protease, known as ubiquitin specific protease 7), one of DUBs, regulates the dynamics of the p53 and Mdm2 network in response to DNA damage by deubiquitinating both p53 and its E3 ubiquitin ligase, Mdm2. Its concerted action increases the level of functional p53 by preventing proteasome-dependent degradation of p53. However, the protein substrates that are targeted by HAUSP to mediate DNA damage responses in the context of the HAUSP-p53-Mdm2 complex are not fully identified. Here, we identified nucleolin as a new substrate for HAUSP by proteomic analysis. Nucleolin has two HAUSP binding sites in its N- and C-terminal regions and the mutation of HAUSP interacting peptides on nucleolin disrupts their interaction and it leads to the increased level of nucleolin ubiquitination. In addition, HAUSP regulates the stability of nucleolin by removing ubiquitin from nucleolin. Nucleolin exists as a component of the HAUSP-p53-Mdm2 complex and both Mdm2 and p53 are required for the interaction between HAUSP and nucleolin. Importantly, the irradiation increases the HAUSP-nucleolin interaction, leading to nucleolin stabilization significantly. Taken together, this study reveals a new component of the HAUSP-p53-Mdm2 complex that governs dynamic cellular responses to DNA damage.