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

Key-Hwan Lim; Jang-Joon Park; Bon-Hee Gu; Jin-Ock Kim; Sang Gyu Park; Kwang-Hyun Baek

doi:10.1038/srep12793

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

Sci Rep. 2015 Aug 4:5:12793. doi: 10.1038/srep12793.

Authors

Key-Hwan Lim¹, Jang-Joon Park¹, Bon-Hee Gu¹, Jin-Ock Kim¹, Sang Gyu Park², Kwang-Hyun Baek¹

Affiliations

¹ Department of Biomedical Science, CHA University, Bundang CHA General Hospital, Gyeonggi-Do 463-400, Republic of Korea.
² College of Pharmacy, Ajou University, Suwon, Gyeonggi-Do 443-749, Republic of Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Annexin A1 / genetics
Annexin A1 / metabolism
DNA Damage / genetics*
Gene Expression Regulation
HCT116 Cells
HEK293 Cells
HeLa Cells
Humans
MCF-7 Cells
Nucleolin
Phosphoproteins / antagonists & inhibitors
Phosphoproteins / genetics*
Phosphoproteins / metabolism
Proteasome Endopeptidase Complex / metabolism
Protein Stability
Proteolysis
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 / genetics*
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism
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-Specific Peptidase 7

Substances

Annexin A1
Phosphoproteins
RNA, Small Interfering
RNA-Binding Proteins
Tumor Suppressor Protein p53
Ubiquitin
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
USP7 protein, human
Ubiquitin Thiolesterase
Ubiquitin-Specific Peptidase 7
Proteasome Endopeptidase Complex