Role for G-Quadruplex RNA Binding by Epstein-Barr Virus Nuclear Antigen 1 in DNA Replication and Metaphase Chromosome Attachment
- 15 October 2009
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 83 (20), 10336-10346
- https://doi.org/10.1128/jvi.00747-09
Abstract
Latent infection by Epstein-Barr virus (EBV) requires both replication and maintenance of the viral genome. EBV nuclear antigen 1 (EBNA1) is a virus-encoded protein that is critical for the replication and maintenance of the genome during latency in proliferating cells. We have previously demonstrated that EBNA1 recruits the cellular origin recognition complex (ORC) through an RNA-dependent interaction with EBNA1 linking region 1 (LR1) and LR2. We now show that LR1 and LR2 bind to G-rich RNA that is predicted to form G-quadruplex structures. Several chemically distinct G-quadruplex-interacting drugs disrupted the interaction between EBNA1 and ORC. The G-quadruplex-interacting compound BRACO-19 inhibited EBNA1-dependent stimulation of viral DNA replication and preferentially blocked proliferation of EBV-positive cells relative to EBV-negative cell lines. BRACO-19 treatment also disrupted the ability of EBNA1 to tether to metaphase chromosomes, suggesting that maintenance function is also mediated through G-quadruplex recognition. These findings suggest that the EBNA1 replication and maintenance function uses a common G-quadruplex binding capacity of LR1 and LR2, which may be targetable by small-molecule inhibitors.This publication has 74 references indexed in Scilit:
- Epstein-Barr Virus Episome Stability Is Coupled to a Delay in Replication TimingJournal of Virology, 2009
- RNA-dependent recruitment of the origin recognition complexThe EMBO Journal, 2008
- Preferential Cytolysis of Peripheral Memory CD4 + T Cells by In Vitro X4-Tropic Human Immunodeficiency Virus Type 1 Infection before the Completion of Reverse TranscriptionJournal of Virology, 2008
- Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regionsBiochimie, 2008
- The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancerNucleic Acids Research, 2008
- Interaction between HMGA1a and the origin recognition complex creates site-specific replication originsProceedings of the National Academy of Sciences of the United States of America, 2008
- The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cellsThe EMBO Journal, 2007
- An RNA G-quadruplex in the 5′ UTR of the NRAS proto-oncogene modulates translationNature Chemical Biology, 2007
- Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genesProceedings of the National Academy of Sciences of the United States of America, 2006
- ORC binding to TRF2 stimulates OriP replicationEMBO Reports, 2006