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Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes
Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936862/ https://www.ncbi.nlm.nih.gov/pubmed/31841561 http://dx.doi.org/10.1371/journal.ppat.1008228 |
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author | Xu, Huanzhou Perez, Ramon D. Frey, Tiffany R. Burton, Eric M. Mannemuddhu, Sudha Haley, John D. McIntosh, Michael T. Bhaduri-McIntosh, Sumita |
author_facet | Xu, Huanzhou Perez, Ramon D. Frey, Tiffany R. Burton, Eric M. Mannemuddhu, Sudha Haley, John D. McIntosh, Michael T. Bhaduri-McIntosh, Sumita |
author_sort | Xu, Huanzhou |
collection | PubMed |
description | Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV’s ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers. |
format | Online Article Text |
id | pubmed-6936862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-69368622020-01-07 Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes Xu, Huanzhou Perez, Ramon D. Frey, Tiffany R. Burton, Eric M. Mannemuddhu, Sudha Haley, John D. McIntosh, Michael T. Bhaduri-McIntosh, Sumita PLoS Pathog Research Article Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV’s ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers. Public Library of Science 2019-12-16 /pmc/articles/PMC6936862/ /pubmed/31841561 http://dx.doi.org/10.1371/journal.ppat.1008228 Text en © 2019 Xu 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Xu, Huanzhou Perez, Ramon D. Frey, Tiffany R. Burton, Eric M. Mannemuddhu, Sudha Haley, John D. McIntosh, Michael T. Bhaduri-McIntosh, Sumita Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title | Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title_full | Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title_fullStr | Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title_full_unstemmed | Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title_short | Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes |
title_sort | novel replisome-associated proteins at cellular replication forks in ebv-transformed b lymphocytes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936862/ https://www.ncbi.nlm.nih.gov/pubmed/31841561 http://dx.doi.org/10.1371/journal.ppat.1008228 |
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