About GSBS   |  FAQ  |  Job Opportunities  |  Search UMDNJ
     




Daxx is a Target for the NEDD8 Pathway

by
Shih-Chieh Tsai
M.S., 1999
National Cheng Kung University
Taiwan, R.O.C.

Student Advisor: J. Don Chen, Ph.D.

Graduate Program in Cellular and Molecular Pharmacology


RWJMS 4th Floor Conference Room

Monday, April 7, 2008
2:00 pm


Abstract

Daxx (death domain-associated protein) is involved in various cellular pathways including apoptosis, transcriptional regulation, DNA remodeling and virus infection. Hence, the functions of Daxx must be precisely regulated by various cellular machineries. Posttranslational modifications have been shown to play important roles in modulating functions of many cellular components. To date, phosphorylation, ubiquitination and sumoylation of Daxx are reported. Herein, we demonstrated that Daxx is modified by NEDD8 (neddylation) and three potential E3 ligases, SPOP-Cullin3 ligase, Mdm2 and PIASy were found for Daxx neddylation. In particular, SPOP-Cullin3 ligase has been reported to promote Daxx polyubiquitination as well. We showed that SPOP-dependant Daxx neddylation was inhibited by NEDD8-specific protease NEDP1. Multiple lysine residues of Daxx were involved in NEDD8 conjugation. The amount of Daxx was elevated under SPOP-mediated neddylation-prominent condition, and the increase of Daxx might be reduced by ubiquitin and vice versa. Upon VP-16 treatment, which could cause DNA damage and apoptosis, SPOP-mediated polyubiquitination was enhanced accompanied with the reduction of Daxx. Conversely, Daxx neddylation by SPOP was decreased upon VP-16 treatment. Furthermore, the cleavage of poly (ADP-ribose) polymerase was not promoted nor suppressed under SPOP-mediated Daxx neddylation-favorable condition. The present study suggested that Daxx is regulated by multiple NEDD8 E3 ligases, while SPOP-Cullin3 ligase might modulate the function of Daxx by both neddylation and ubiquitination in response to DNA damage.


Return to Dissertation list

 

Newark Campus - Piscataway Campus - Stratford Campus
About GSBS - FAQ - Job Opportunities - Search UMDNJ