Abstract
DNA damage can occur through diverse stimulations such as toxins, drugs, and environmental factors. To respond to DNA damage, mammalian cells induce DNA damage response (DDR). DDR signal activates a rapid signal transduction pathway, regulating the cell fate based on the damaged cell condition. Moreover, serious damaged cells have to be eliminated by the macrophage to maintain homeostasis. Because the DDR induces genomic instability followed by tumor formation, targeting the DDR signaling can be applied for the cancer therapy. Herpes virus-associated ubiquitin-specific protease (HAUSP/USP7) is one of the well-known deubiquitinating enzymes (DUBs) owing to its relevance with Mdm2-p53 complex. The involvement of HAUSP in DDR through p53 led us to investigate novel substrates for HAUSP, which is related to DDR or apoptosis. As a result, we identified annexin-1 (ANXA1) as one of the putative substrates for HAUSP. ANXA1 has numerous roles in cellular systems including anti-inflammation, damage response, and apoptosis. Several studies have demonstrated that ANXA1 can be modified in a post-translational manner by processes such as phosphorylation, SUMOylation, and ubiquitination. In addition, DNA damage gives various functions to ANXA1 such as stress response or cleavage-mediated apoptotic cell clearance. In the current study, our proteomic analysis using two-dimensional electrophoresis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) and nano LC-MS/MS, and immunoprecipitation revealed that ANXA1 binds to HAUSP through its HAUSP-binding motif (P/AXXS), and the cleavage and damage-responsive functions of ANXA1 upon UV-induced DNA damage may be followed by HAUSP-mediated deubiquitination of ANXA1. Intriguingly, the UV-induced damage responses via HAUSP-ANXA1 interaction in HeLa cells were different from the responses shown in the Jurkat cells, suggesting that their change of roles may depend on the cell types.
Highlights
HAUSP, known as USP7, is a member of the ubiquitinspecific proteases (USPs) family of deubiquitinating enzymes (DUBs)
We found several putative substrates, some of which are known to be involved in apoptosis or DNA damage response (DDR)
We suggest that ANXA1 functions of UV-induced DDR are regulated by the deubiquitinating activity of HAUSP
Summary
HAUSP, known as USP7, is a member of the USP family of DUBs. The importance of HAUSP in cells was demonstrated by its ability to recognize and deubiquitinate both the tumor suppressor p53 and Mdm[2], a p53-specific E3 ligase. We found several putative substrates, some of which are known to be involved in apoptosis or DNA damage response (DDR). The biological functions of ANXA1 are extensively studied: anti-inflammatory mediator,[14,15] relationship with tumorigenesis,[16] DDR,[17,18] and involvement in apoptosis and apoptotic cell clearance.[19,20] Another important feature of ANXA1 activity is the cleavage of the N-terminal region of ANXA1. We suggest that ANXA1 functions of UV-induced DDR are regulated by the deubiquitinating activity of HAUSP
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