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Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality

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 topoisome...

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Autores principales: Chang, Yu-Hsin, Lee, Chung-Pei, Su, Mei-Tzu, Wang, Jiin-Tarng, Chen, Jen-Yang, Lin, Su-Fang, Tsai, Ching-Hwa, Hsieh, Min-Jei, Takada, Kenzo, Chen, Mei-Ru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387188/
https://www.ncbi.nlm.nih.gov/pubmed/22768064
http://dx.doi.org/10.1371/journal.pone.0039217
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author Chang, Yu-Hsin
Lee, Chung-Pei
Su, Mei-Tzu
Wang, Jiin-Tarng
Chen, Jen-Yang
Lin, Su-Fang
Tsai, Ching-Hwa
Hsieh, Min-Jei
Takada, Kenzo
Chen, Mei-Ru
author_facet Chang, Yu-Hsin
Lee, Chung-Pei
Su, Mei-Tzu
Wang, Jiin-Tarng
Chen, Jen-Yang
Lin, Su-Fang
Tsai, Ching-Hwa
Hsieh, Min-Jei
Takada, Kenzo
Chen, Mei-Ru
author_sort Chang, Yu-Hsin
collection PubMed
description 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.
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spelling pubmed-33871882012-07-05 Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality Chang, Yu-Hsin Lee, Chung-Pei Su, Mei-Tzu Wang, Jiin-Tarng Chen, Jen-Yang Lin, Su-Fang Tsai, Ching-Hwa Hsieh, Min-Jei Takada, Kenzo Chen, Mei-Ru PLoS One Research Article 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. Public Library of Science 2012-06-29 /pmc/articles/PMC3387188/ /pubmed/22768064 http://dx.doi.org/10.1371/journal.pone.0039217 Text en Chang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chang, Yu-Hsin
Lee, Chung-Pei
Su, Mei-Tzu
Wang, Jiin-Tarng
Chen, Jen-Yang
Lin, Su-Fang
Tsai, Ching-Hwa
Hsieh, Min-Jei
Takada, Kenzo
Chen, Mei-Ru
Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title_full Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title_fullStr Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title_full_unstemmed Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title_short Epstein-Barr Virus BGLF4 Kinase Retards Cellular S-Phase Progression and Induces Chromosomal Abnormality
title_sort epstein-barr virus bglf4 kinase retards cellular s-phase progression and induces chromosomal abnormality
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387188/
https://www.ncbi.nlm.nih.gov/pubmed/22768064
http://dx.doi.org/10.1371/journal.pone.0039217
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