title: Epstein-Barr virus BGLF4 kinase retards cellular S-phase progression and induces chromosomal abnormality.
abstract: Epstein-Barr virus (EBV) induces an uncoordinated S-phase-like cellular environment coupled with multiple prophase-like events in cells replicating the virus. The EBV encoded Ser/Thr kinase BGLF4 has been shown to induce premature chromosome condensation through activation of condensin and topoisomerase II and reorganization of the nuclear lamina to facilitate the nuclear egress of nucleocapsids in a pathway mimicking Cdk1. However, the observation that RB is hyperphosphorylated in the presence of BGLF4 raised the possibility that BGLF4 may have a Cdk2-like activity to promote S-phase progression. Here, we investigated the regulatory effects of BGLF4 on cell cycle progression and found that S-phase progression and DNA synthesis were interrupted by BGLF4 in mammalian cells. Expression of BGLF4 did not compensate Cdk1 defects for DNA replication in S. cerevisiae. Using time-lapse microscopy, we found the fate of individual HeLa cells was determined by the expression level of BGLF4. In addition to slight cell growth retardation, BGLF4 elicits abnormal chromosomal structure and micronucleus formation in 293 and NCP-TW01 cells. In Saos-2 cells, BGLF4 induced the hyperphosphorylation of co-transfected RB, while E2F1 was not released from RB-E2F1 complexes. The E2F1 regulated activities of the cyclin D1 and ZBRK1 promoters were suppressed by BGLF4 in a dose dependent manner. Detection with phosphoamino acid specific antibodies revealed that, in addition to Ser780, phosphorylation of the DNA damage-responsive Ser612 on RB was enhanced by BGLF4. Taken together, our study indicates that BGLF4 may directly or indirectly induce a DNA damage signal that eventually interferes with host DNA synthesis and delays S-phase progression.
authors: Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yu-Hsin
authors: YH
authors: Chang
authors: Chung-Pei
authors: CP
authors: Lee
authors: Mei-Tzu
authors: MT
authors: Su
authors: Jiin-Tarng
authors: JT
authors: Wang
authors: Jen-Yang
authors: JY
authors: Chen
authors: Su-Fang
authors: SF
authors: Lin
authors: Ching-Hwa
authors: CH
authors: Tsai
authors: Min-Jei
authors: MJ
authors: Hsieh
authors: Kenzo
authors: K
authors: Takada
authors: Mei-Ru
authors: MR
authors: Chen
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism; D016193:G1 Phase; D042822:Genomic Instability; D004854:Herpesvirus 4, Human / Q000201:enzymology*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013696:Temperature; D013936:Thymidine / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D014764:Viral Proteins; D004247:DNA; C406063:BGLF4 protein, Epstein-Barr virus; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D013936:Thymidine