The Epstein-Barr Virus BMRF1 Protein Activates Transcription and Inhibits the DNA Damage Response by Binding NuRD.
Antigens, Viral
/ genetics
Cell Line, Tumor
DNA Damage
DNA Replication
DNA, Viral
/ genetics
DNA-Binding Proteins
/ metabolism
Epstein-Barr Virus Infections
/ virology
HEK293 Cells
HeLa Cells
Herpesvirus 4, Human
/ genetics
Humans
Membrane Glycoproteins
/ metabolism
Mi-2 Nucleosome Remodeling and Deacetylase Complex
/ metabolism
Promoter Regions, Genetic
Signal Transduction
Trans-Activators
/ metabolism
Transcriptional Activation
Viral Proteins
/ metabolism
Virus Replication
BMRF1
Epstein-Barr virus
NuRD
RNF168
double-stranded break signaling
transactivation
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
15 11 2019
15 11 2019
Historique:
received:
25
06
2019
accepted:
16
08
2019
pubmed:
30
8
2019
medline:
21
7
2020
entrez:
30
8
2019
Statut:
epublish
Résumé
The BMRF1 protein of Epstein-Barr virus (EBV) has multiple roles in viral lytic infection, including serving as the DNA polymerase processivity factor, activating transcription from several EBV promoters and inhibiting the host DNA damage response to double-stranded DNA breaks (DSBs). Using affinity purification coupled to mass spectrometry, we identified the nucleosome remodeling and deacetylation (NuRD) complex as the top interactor of BMRF1. We further found that NuRD components localize with BMRF1 at viral replication compartments and that this interaction occurs through the BMRF1 C-terminal region previously shown to mediate transcriptional activation. We identified an RBBP4 binding motif within this region that can interact with both RBBP4 and MTA2 components of the NuRD complex and showed that point mutation of this motif abrogates NuRD binding as well as the ability of BMRF1 to activate transcription from the BDLF3 and BLLF1 EBV promoters. In addition to its role in transcriptional regulation, NuRD has been shown to contribute to DSB signaling in enabling recruitment of RNF168 ubiquitin ligase and subsequent ubiquitylation at the break. We showed that BMRF1 inhibited RNF168 recruitment and ubiquitylation at DSBs and that this inhibition was at least partly relieved by loss of the NuRD interaction. The results reveal a mechanism by which BMRF1 activates transcription and inhibits DSB signaling and a novel role for NuRD in transcriptional activation in EBV.
Identifiants
pubmed: 31462557
pii: JVI.01070-19
doi: 10.1128/JVI.01070-19
pmc: PMC6819917
pii:
doi:
Substances chimiques
Antigens, Viral
0
BMRF-2 protein, Human herpesvirus 4
0
DNA, Viral
0
DNA-Binding Proteins
0
Epstein-Barr virus early antigen diffuse component
0
Membrane Glycoproteins
0
Trans-Activators
0
Viral Proteins
0
Mi-2 Nucleosome Remodeling and Deacetylase Complex
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : 153014
Pays : Canada
Organisme : CIHR
ID : 152948
Pays : Canada
Informations de copyright
Copyright © 2019 American Society for Microbiology.
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