scholarly journals The immediate early protein 1 of the human herpesvirus 6B counteracts NBS1 and prevents homologous recombination repair pathways

2021 ◽  
Author(s):  
Vanessa Collin ◽  
Elise Biquand ◽  
Vincent Tremblay ◽  
Elise G Lavoie ◽  
Julien Dessapt ◽  
...  
Keyword(s):  
Viral Replication ◽  
Genomic Instability ◽  
Human Herpesvirus ◽  
Strand Break ◽  
Host Cells ◽  
Immediate Early ◽  
Telomeric Sequence ◽  
Telomeric Sequences ◽  
Early Protein ◽  
Repair Mechanisms

Integration of viral DNA in the genome of host cells triggers host-pathogens interaction that are consequential for the virus and the infected cells. In cells semi-permissive for viral replication, the human herpesvirus 6B (HHV-6B) integrates its genome into the host telomeric sequences. Interestingly, HHV-6B integration in gametes leads to a condition called inherited chromosomally integrated HHV-6B (iciHHV-6B), where the newborn carries a copy of HHV-6B in every cell of its body and is associated with health issues such as spontaneous abortion rates, pre-eclampsia and angina pectoris when transmitted to its offspring. Unlike retroviruses, the mechanism that leads to viral integration of DNA viruses and the consequences of these events on host cells are not well characterized. Here, we report that HHV-6B infection induce genomic instability by suppressing the ability of the host cell to sense DNA double-strand break (DSB). We discovered that this phenotype is mediated by the ability of the immediate-early HHV-6B protein IE1 to bind, delocalize, and inhibit the functions of the DNA damage sensor NBS1. These results raise the possibility that the genomic instability induced by the expression of IE1 from integrated genomes contributes to the development of iciHHV-6B-associated disease. As reported for other types of viruses, the inhibition of DSB sensing and signaling promotes viral replication. However, HHV-6B integration is not affected when this pathway is inhibited, supporting models where integration of the viral genome at telomeric sequence is dictated by mechanisms that promote telomere-elongation in a given infected cell and not solely DNA repair mechanisms.

scholarly journals Mutational analysis of varicella-zoster virus (VZV) immediate early protein (IE62) subdomains and their importance in viral replication

Virology ◽  
2016 ◽  
Vol 492 ◽  
pp. 82-91 ◽  
Author(s):  
Mohamed I. Khalil ◽  
Xibing Che ◽  
Phillip Sung ◽  
Marvin H. Sommer ◽  
John Hay ◽  
...  
Keyword(s):  
Viral Replication ◽  
Varicella Zoster Virus ◽  
Mutational Analysis ◽  
Immediate Early ◽  
Varicella Zoster ◽  
Early Protein

scholarly journals Crystal Structure of the DNA-Binding Domain of Human Herpesvirus 6A Immediate Early Protein 2

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Mitsuhiro Nishimura ◽  
Junjie Wang ◽  
Aika Wakata ◽  
Kento Sakamoto ◽  
Yasuko Mori
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Site ◽  
Human Herpesvirus ◽  
Binding Domain ◽  
Immediate Early ◽  
Dna Binding Domain ◽  
Factor Binding ◽  
Early Protein ◽  
Dna Binding Site

ABSTRACT Immediate early proteins of human herpesvirus 6A (HHV-6A) are expressed at the outset of lytic infection and thereby regulate viral gene expression. Immediate early protein 2 (IE2) of HHV-6A is a transactivator that drives a variety of promoters. The C-terminal region of HHV-6A IE2 is shared among IE2 homologs in betaherpesviruses and is involved in dimerization, DNA binding, and transcription factor binding. In this study, the structure of the IE2 C-terminal domain (IE2-CTD) was determined by X-ray crystallography at a resolution of 2.5 Å. IE2-CTD forms a homodimer stabilized by a β-barrel core with two interchanging long loops. Unexpectedly, the core structure resembles those of the gammaherpesvirus factors EBNA1 of Epstein-Barr virus and LANA of Kaposi sarcoma-associated herpesvirus, but the interchanging loops are longer in IE2-CTD and form helix-turn-helix (HTH)-like motifs at their tips. The HTH and surrounding α-helices form a structural feature specific to the IE2 group. The apparent DNA-binding site (based on structural similarity with EBNA1 and LANA) resides on the opposite side of the HTH-like motifs, surrounded by positive electrostatic potential. Mapping analysis of conserved residues on the three-dimensional structure delineated a potential factor-binding site adjacent to the expected DNA-binding site. The predicted bi- or tripartite functional sites indicate a role for IE2-CTD as an adapter connecting the promoter and transcriptional factors that drive gene expression. IMPORTANCE Human herpesvirus 6A (HHV-6A) and HHV-6B belong to betaherpesvirus subfamily. Both viruses establish lifelong latency after primary infection, and their reactivation poses a significant risk to immunocompromised patients. Immediate early protein 2 (IE2) of HHV-6A and HHV-6B is a transactivator that triggers viral replication and contains a DNA-binding domain shared with other betaherpesviruses such as human herpesvirus 7 and human cytomegalovirus. In this study, an atomic structure of the DNA-binding domain of HHV-6A IE2 was determined and analyzed, enabling a structure-based understanding of the functions of IE2, specifically DNA recognition and interaction with transcription factors. Unexpectedly, the dimeric core resembles the DNA-binding domain of transcription regulators from gammaherpesviruses, showing structural conservation as a DNA-binding domain but with its own unique structural features. These findings facilitate further characterization of this key viral transactivator.

The immediate early protein WSV187 can influence viral replication via regulation of JAK/STAT pathway in Drosophila

2017 ◽  
Vol 72 ◽  
pp. 89-96 ◽  
Author(s):  
Changkun Pan ◽  
Wei Wang ◽  
Huifang Yuan ◽  
Lirong Yang ◽  
Baoru Chen ◽  
...  
Keyword(s):  
Viral Replication ◽  
Immediate Early ◽  
Early Protein ◽  
Stat Pathway

scholarly journals Recognition of a Novel Stage of Betaherpesvirus Latency in Human Herpesvirus 6

2003 ◽  
Vol 77 (3) ◽  
pp. 2258-2264 ◽  
Author(s):  
Kazuhiro Kondo ◽  
Junji Sashihara ◽  
Kazuya Shimada ◽  
Masaya Takemoto ◽  
Kiyoko Amo ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Intermediate Stage ◽  
Viral Reactivation ◽  
Immediate Early ◽  
Human Herpesvirus 6 ◽  
Early Protein ◽  
Stable Intermediate ◽  
Herpesvirus 6

ABSTRACT Latency-associated transcripts of human herpesvirus 6 (H6LTs) (K. Kondo et al. J. Virol. 76:4145-4151, 2002) were maximally expressed at a fairly stable intermediate stage between latency and reactivation both in vivo and in vitro. H6LTs functioned as sources of immediate-early protein 1 at this stage, which up-regulated the viral reactivation.

scholarly journals Telomeric-Like Repeats Flanked by Sequences Retrotranscribed from the Telomerase RNA Inserted at DNA Double-Strand Break Sites during Vertebrate Genome Evolution

2021 ◽  
Vol 22 (20) ◽  
pp. 11048
Author(s):  
Lorenzo Sola ◽  
Solomon G. Nergadze ◽  
Eleonora Cappelletti ◽  
Francesca M. Piras ◽  
Elena Giulotto ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Telomerase Rna ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Telomeric Sequences ◽  
Dna Double Strand Break ◽  
Interstitial Telomeric Sequences ◽  
Repair Mechanisms ◽  
One Step

Interstitial telomeric sequences (ITSs) are stretches of telomeric-like repeats located at internal chromosomal sites. We previously demonstrated that ITSs have been inserted during the repair of DNA double-strand breaks in the course of evolution and that some rodent ITSs, called TERC-ITSs, are flanked by fragments retrotranscribed from the telomerase RNA component (TERC). In this work, we carried out an extensive search of TERC-ITSs in 30 vertebrate genomes and identified 41 such loci in 22 species, including in humans and other primates. The fragment retrotranscribed from the TERC RNA varies in different lineages and its sequence seems to be related to the organization of TERC. Through comparative analysis of TERC-ITSs with orthologous empty loci, we demonstrated that, at each locus, the TERC-like sequence and the ITS have been inserted in one step in the course of evolution. Our findings suggest that telomerase participated in a peculiar pathway of DNA double-strand break repair involving retrotranscription of its RNA component and that this mechanism may be active in all vertebrate species. These results add new evidence to the hypothesis that RNA-templated DNA repair mechanisms are active in vertebrate cells.

scholarly journals The Epstein-Barr Virus Immediate-Early Protein BZLF1 Induces both a G2 and a Mitotic Block

2002 ◽  
Vol 76 (19) ◽  
pp. 10030-10037 ◽  
Author(s):  
Amy Mauser ◽  
Elizabeth Holley-Guthrie ◽  
Dennis Simpson ◽  
William Kaufmann ◽  
Shannon Kenney
Keyword(s):  
Epstein Barr Virus ◽  
Cyclin B1 ◽  
Lytic Infection ◽  
Host Cells ◽  
Immediate Early ◽  
Barr Virus ◽  
Early Protein ◽  
Mitotic Block ◽  
Epstein Barr ◽  
Mitotic Defect

ABSTRACT The Epstein-Barr virus immediate-early protein BZLF1 is a transcriptional activator that mediates the switch from latent to lytic infection. Here we demonstrate that BZLF1 induces both a G2 block and a mitotic block in HeLa cells and inhibits chromosome condensation. While the G2 block is associated with decreased cyclin B1 in host cells and can be rescued by overexpression of cyclin B1, the mechanism for the mitotic defect is as yet undetermined.

scholarly journals H2B homology region of major immediate–early protein 1 is essential for murine cytomegalovirus to disrupt nuclear domain 10, but is not important for viral replication in cell culture

2011 ◽  
Vol 92 (9) ◽  
pp. 2006-2019 ◽  
Author(s):  
Ruth Cosme-Cruz ◽  
Francisco Puerta Martínez ◽  
Kareni J. Perez ◽  
Qiyi Tang
Keyword(s):  
Cell Culture ◽  
Viral Replication ◽  
Point Mutations ◽  
Mouse Cell ◽  
Immediate Early ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Early Protein ◽  
Nuclear Domain ◽  
Human Cmv

Cytomegalovirus (CMV) major immediate–early protein 1 (IE1) has multiple functions and is important for efficient viral infection. As does its counterpart in human CMV, murine CMV (MCMV) IE1 also functions as a disruptor of mouse-cell nuclear domain 10 (ND10), where many different gene-regulation proteins congregate. It still remains unclear how MCMV IE1 disperses ND10 and whether this dispersion could have any effect on viral replication. MCMV IE1 is 595 aa long and has multiple functional domains that have not yet been fully analysed. In this study, we dissected the IE1 molecule by truncation and/or deletion and found that the H2B homology domain (amino acid sequence NDIFERI) is required for the dispersion of ND10 by IE1. Furthermore, we made additional deletions and point mutations and found that the minimal truncation in the H2B homology domain required for IE1 to lose the ability to disperse ND10 is just 3 aa (IFE). Surprisingly, the mutated IE1 still interacted with PML and co-localized with ND10 but failed to disperse ND10. This suggests that binding to ND10 key protein is essential to, but not sufficient for, the dispersal of ND10, and that some other unknown mechanism must be involved in this biological procedure. Finally, we generated MCMV with IFE-deleted IE1 (MCMVdlIFE) and its revertant (MCMVIFERQ). Although MCMVdlIFE lost the ability to disperse ND10, plaque assays and viral gene production assays showed that the deletion of IFE did not increase viral replication in cell culture. We conclude that the dispersion of ND10 appears not to be important for MCMV replication in a mouse-cell culture.

scholarly journals Epstein-Barr Virus Immediate-Early Protein BRLF1 Interacts with CBP, Promoting Enhanced BRLF1 Transactivation

2001 ◽  
Vol 75 (13) ◽  
pp. 6228-6234 ◽  
Author(s):  
Jennifer J. Swenson ◽  
Elizabeth Holley-Guthrie ◽  
Shannon C. Kenney
Keyword(s):  
Viral Replication ◽  
Epstein Barr Virus ◽  
Immediate Early ◽  
Transcriptional Activators ◽  
Creb Binding Protein ◽  
Raji Cells ◽  
Barr Virus ◽  
Early Protein ◽  
Epstein Barr ◽  
Multiple Domains

ABSTRACT The Epstein-Barr virus (EBV) immediate-early protein BRLF1 is a transcriptional activator that mediates the switch from latent to lytic viral replication. Many transcriptional activators function, in part, due to an interaction with histone acetylases, such as CREB-binding protein (CBP). Here we demonstrate that BRLF1 interacts with the amino and carboxy termini of CBP and that multiple domains of the BRLF1 protein are necessary for this interaction. Furthermore, we show that the interaction between BRLF1 and CBP is important for BRLF1-induced activation of the early lytic EBV gene SM in Raji cells.

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