Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation

PLoS Pathogens

Paul M. Lieberman¹  Nicholas Paparoidamis¹  Shannon Kenney²  Kayla A. Martin³  Fang Lu³  Nadezhda Tikhmyanova³  Steve Tutton³  Joseph M. Salvino³  Andrew V. Kossenkov³ 

[1] Drexel University, College of Medicine, Department of Pharmacology, Philadelphia, Pennsylvania, United States of America;The University of Wisconsin, School of Medicine and Public Health at Madison, McCardle Laboratory for Cancer Research, Departments of Oncology and Medicine, Madison, Wisconsin, United States of America;The Wistar Institute, Program in Gene Expression and Regulation, Philadelphia, Pennsylvania, United States of America

关键词: DNA transcription;    Library screening;    293T cells;    Epstein-Barr virus;    DNA damage;    Actins;    Viral replication;    Lentivirus;   

DOI  :  10.1371/journal.ppat.1006517

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.

【 授权许可】

CC BY