Epstein-Barr Virus BGLF4 Kinase Induces Premature Chromosome Condensation through Activation of Condensin and Topoisomerase II

Abstract

Previous studies of Epstein-Barr virus (EBV) replication focused mainly on the viral and cellular factors involved in replication compartment assembly and controlling the cell cycle. However, little is known about how EBV reorganizes nuclear architecture and the chromatin territories. In EBV-positive nasopharyngeal carcinoma NA cells or Akata cells, we noticed that cellular chromatin becomes highly condensed upon EBV reactivation. In searching for the possible mechanisms involved, we found that transient expression of EBV BGLF4 kinase induces unscheduled chromosome condensation, nuclear lamina disassembly, and stress fiber rearrangements, independently of cellular DNA replication and Cdc2 activity. BGLF4 interacts with condensin complexes, the major components in mitotic chromosome assembly, and induces condensin phosphorylation at Cdc2 consensus motifs. BGLF4 also stimulates the decatenation activity of topoisomerase II, suggesting that it may induce chromosome condensation through condensin and topoisomerase II activation. The ability to induce chromosome condensation is conserved in another gammaherpesvirus kinase, murine herpesvirus 68 ORF36. Together, these findings suggest a novel mechanism by which gammaherpesvirus kinases may induce multiple premature mitotic events to provide more extrachromosomal space for viral DNA replication and successful egress of nucleocapsid from the nucleus.DNA viruses adopt various strategies to facilitate their replication and maturation within host cells, including usurping the cellular DNA replication machinery and taking over the nuclear space for viral DNA replication, transcription, and packaging. Small DNA viruses, such as simian virus 40 and papillomaviruses, modulate the cell cycle control pathway and promote entry into S phase. This enables the host DNA polymerase and the increased nucleotide pool to be used for virus replication. For large DNA viruses, such as herpesviruses, which encode DNA replication and nucleotide metabolism enzymes, the viral DNA replication strategy is controlled through even more sophisticated interactions between host and viral machineries (reviewed in references 36 and 57).Epstein-Barr virus (EBV) belongs to the Gammaherpesvirinae and infects most of the human population worldwide. Infection may cause infectious mononucleosis and is closely associated with human malignant diseases, such as nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (61). Two different mechanisms have evolved to sustain successful infection of EBV. After primary infection, EBV becomes latent and the virally encoded EBNA-1 ensures that the circular episomal genome replicates during the S phase of the cell cycle and partitions equally into the daughter cells at mitosis (38). Upon immunoglobulin (Ig) cross-linking or chemical stimulation, EBV can be reactivated and express two immediate-early transactivators, Zta and Rta, which then turn on a cascade of viral gene expression to initiate lytic virus replication. Simultaneously, Zta and Rta may also modulate the cell c...

Chromosome Aberrations as a Biomarker for Genomic Instability in Cell Cultures Originated From Bovines, Canines and Equines Infected With Papillomavirus

“…To date, the PCC had not been registered with the papillomavirus infection but with Sendai Virus (SV) infections and more recently with EBV (Ito et al, 2002;Lee et al, 2007). Thus, for the first time the presence of PCC in cells infected with PV in bovines, canines and equines were demonstrated.…”

“…The PCC findings, mostly performed in the S phase, and according to studies of Duelli and Lazebnik (2007), refer to multiple DNA breaks resulting in multiple chromosomal fragments attesting the pulverized appearance of the cell. According to reports of Lee et al, (2007), the chromatin of nasopharyngeal carcinoma cells became highly condensed when positive Epstein-Barr Virus (EBV). Similarly, the chromatin of adenocarcinoma cells in canine and bovine papilloma infected cells showed high levels of PCC.…”

“…In conjunction with cdc2, cyclin A and B regulate the entry into cell mitosis (Pines, 1996 cited Thompson et al, 1997). The activation of cdc2 is mediated by a complex starting with the increase of cyclin B1 in the S and G2 phase in the presence of Epstain-Barr virus (EBV) (Lee et al, 2007). The cyclin-dependent kinase activity in the S phase increases during viral replication, while the cell DNA replication is inhibited.…”

“…The cyclin-dependent kinase activity in the S phase increases during viral replication, while the cell DNA replication is inhibited. Genetic and biochemical evidence suggests that the condensed complex of protein subunits and DNA topoisomerase II, essential for mitotic condensation, both developed important role in the assembly and organization of mitotic chromosomes (Lee et al, 2007).…”

“…From the mid-70s, the PCC has been recognized as a tool for the investigation of chromosomal dynamics in radioactive cytogenetic and chromosome replication studies (Gotoh and Durante, 2006). Condensinas, histone H1, kinase and topoisomerase II (TOPO II) are some molecules occurring in cell induction mechanism of PCC (Lee et al, 2007).…”