Bromodomain Protein Brd4 Plays a Key Role in Merkel Cell Polyomavirus DNA Replication

PLoS Pathogens

Xin Wang¹  Jianxin You¹  Jing Li¹  Jing Jiao¹  Rachel M. Schowalter²  Christopher B. Buck² 

[1] Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America;Tumor Virus Molecular Biology Section, Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, United States of America

关键词: DNA replication;    Viral replication;    293T cells;    SV40;    Cell staining;    Viral replication complex;    Plasmid construction;    Cell cycle;    cell division;   

DOI  :  10.1371/journal.ppat.1003021

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Merkel cell polyomavirus (MCV or MCPyV) is the first human polyomavirus to be definitively linked to cancer. The mechanisms of MCV-induced oncogenesis and much of MCV biology are largely unexplored. In this study, we demonstrate that bromodomain protein 4 (Brd4) interacts with MCV large T antigen (LT) and plays a critical role in viral DNA replication. Brd4 knockdown inhibits MCV replication, which can be rescued by recombinant Brd4. Brd4 colocalizes with the MCV LT/replication origin complex in the nucleus and recruits replication factor C (RFC) to the viral replication sites. A dominant negative inhibitor of the Brd4-MCV LT interaction can dissociate Brd4 and RFC from the viral replication complex and abrogate MCV replication. Furthermore, obstructing the physiologic interaction between Brd4 and host chromatin with the chemical compound JQ1(+) leads to enhanced MCV DNA replication, demonstrating that the role of Brd4 in MCV replication is distinct from its role in chromatin-associated transcriptional regulation. Our findings demonstrate mechanistic details of the MCV replication machinery; providing novel insight to elucidate the life cycle of this newly discovered oncogenic DNA virus.

【 授权许可】

CC BY