title: HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response.
abstract: 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.
authors.affiliation: Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Key-Hwan
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Jang-Joon
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Bon-Hee
authors.initials: BH
authors.lastname: Gu
authors.affiliation: Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Jin-Ock
authors.initials: JO
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyeonggi-Do 443-749, Republic of Korea.
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Baek
mesh_terms: D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D000097796:Nucleolin
chemical_list: D017305:Annexin A1; D010750:Phosphoproteins; D046988:Proteasome Endopeptidase Complex; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D000097796:Nucleolin; C497206:MDM2 protein, human; C464569:USP7 protein, human