Brd4 Is Displaced from HPV Replication Factories as They Expand and Amplify Viral DNA
Identifieur interne : 000190 ( Ncbi/Merge ); précédent : 000189; suivant : 000191Brd4 Is Displaced from HPV Replication Factories as They Expand and Amplify Viral DNA
Auteurs : Nozomi Sakakibara [États-Unis] ; Dan Chen [États-Unis] ; Moon Kyoo Jang [États-Unis] ; Dong Wook Kang [États-Unis] ; Hans F. Luecke [États-Unis] ; Shwu-Yuan Wu [États-Unis] ; Cheng-Ming Chiang [États-Unis] ; Alison A. Mcbride [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2013.
Abstract
Replication foci are generated by many viruses to concentrate and localize viral DNA synthesis to specific regions of the cell. Expression of the HPV16 E1 and E2 replication proteins in keratinocytes results in nuclear foci that recruit proteins associated with the host DNA damage response. We show that the Brd4 protein localizes to these foci and is essential for their formation. However, when E1 and E2 begin amplifying viral DNA, Brd4 is displaced from the foci and cellular factors associated with DNA synthesis and homologous recombination are recruited. Differentiated HPV-infected keratinocytes form similar nuclear foci that contain amplifying viral DNA. We compare the different foci and show that, while they have many characteristics in common, there is a switch between early Brd4-dependent foci and mature Brd4-independent replication foci. However, HPV genomes encoding mutated E2 proteins that are unable to bind Brd4 can replicate and amplify the viral genome. We propose that, while E1, E2 and Brd4 might bind host chromatin at early stages of infection, there is a temporal and functional switch at later stages and increased E1 and E2 levels promote viral DNA amplification, displacement of Brd4 and growth of a replication factory. The concomitant DNA damage response recruits proteins required for DNA synthesis and repair, which could then be utilized for viral DNA replication. Hence, while Brd4 can enhance replication by concentrating viral processes in specific regions of the host nucleus, this interaction is not absolutely essential for HPV replication.
Url:
DOI: 10.1371/journal.ppat.1003777
PubMed: 24278023
PubMed Central: 3836737
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<front><div type="abstract" xml:lang="en"><p>Replication foci are generated by many viruses to concentrate and localize viral DNA synthesis to specific regions of the cell. Expression of the HPV16 E1 and E2 replication proteins in keratinocytes results in nuclear foci that recruit proteins associated with the host DNA damage response. We show that the Brd4 protein localizes to these foci and is essential for their formation. However, when E1 and E2 begin amplifying viral DNA, Brd4 is displaced from the foci and cellular factors associated with DNA synthesis and homologous recombination are recruited. Differentiated HPV-infected keratinocytes form similar nuclear foci that contain amplifying viral DNA. We compare the different foci and show that, while they have many characteristics in common, there is a switch between early Brd4-dependent foci and mature Brd4-independent replication foci. However, HPV genomes encoding mutated E2 proteins that are unable to bind Brd4 can replicate and amplify the viral genome. We propose that, while E1, E2 and Brd4 might bind host chromatin at early stages of infection, there is a temporal and functional switch at later stages and increased E1 and E2 levels promote viral DNA amplification, displacement of Brd4 and growth of a replication factory. The concomitant DNA damage response recruits proteins required for DNA synthesis and repair, which could then be utilized for viral DNA replication. Hence, while Brd4 can enhance replication by concentrating viral processes in specific regions of the host nucleus, this interaction is not absolutely essential for HPV replication.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24278023</article-id>
<article-id pub-id-type="pmc">3836737</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-13-02199</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1003777</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Brd4 Is Displaced from HPV Replication Factories as They Expand and Amplify Viral DNA</article-title>
<alt-title alt-title-type="running-head">Brd4 and HPV Replication</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Sakakibara</surname>
<given-names>Nozomi</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn1"><sup>¤a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Dan</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jang</surname>
<given-names>Moon Kyoo</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kang</surname>
<given-names>Dong Wook</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn2"><sup>¤b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Luecke</surname>
<given-names>Hans F.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wu</surname>
<given-names>Shwu-Yuan</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chiang</surname>
<given-names>Cheng-Ming</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McBride</surname>
<given-names>Alison A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Imperiale</surname>
<given-names>Michael J.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of Michigan, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>amcbride@nih.gov</email>
</corresp>
<fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: AAM NS. Performed the experiments: AAM NS DC MKJ. Analyzed the data: AAM NS. Contributed reagents/materials/analysis tools: CMC HFL SYW DWK. Wrote the paper: AAM.</p>
</fn>
<fn id="fn1" fn-type="current-aff"><label>¤a</label>
<p>Current address: Office of Vaccine Research and Review, Center for Biologics Evaluation and Research Food and Drug Administration, Bethesda, Maryland, United States of America.</p>
</fn>
<fn id="fn2" fn-type="current-aff"><label>¤b</label>
<p>Current address: Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Kyeongsan-si, Kyeongsangbuk-do, South Korea.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>11</month>
<year>2013</year>
</pub-date>
<pmc-comment> Fake ppub added to accomodate plos workflow change from 03/2008 and 03/2009 </pmc-comment>
<pub-date pub-type="ppub"><month>11</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>21</day>
<month>11</month>
<year>2013</year>
</pub-date>
<volume>9</volume>
<issue>11</issue>
<elocation-id>e1003777</elocation-id>
<history><date date-type="received"><day>17</day>
<month>8</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>4</day>
<month>10</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-year>2013</copyright-year>
<license><license-p>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.</license-p>
</license>
</permissions>
<abstract><p>Replication foci are generated by many viruses to concentrate and localize viral DNA synthesis to specific regions of the cell. Expression of the HPV16 E1 and E2 replication proteins in keratinocytes results in nuclear foci that recruit proteins associated with the host DNA damage response. We show that the Brd4 protein localizes to these foci and is essential for their formation. However, when E1 and E2 begin amplifying viral DNA, Brd4 is displaced from the foci and cellular factors associated with DNA synthesis and homologous recombination are recruited. Differentiated HPV-infected keratinocytes form similar nuclear foci that contain amplifying viral DNA. We compare the different foci and show that, while they have many characteristics in common, there is a switch between early Brd4-dependent foci and mature Brd4-independent replication foci. However, HPV genomes encoding mutated E2 proteins that are unable to bind Brd4 can replicate and amplify the viral genome. We propose that, while E1, E2 and Brd4 might bind host chromatin at early stages of infection, there is a temporal and functional switch at later stages and increased E1 and E2 levels promote viral DNA amplification, displacement of Brd4 and growth of a replication factory. The concomitant DNA damage response recruits proteins required for DNA synthesis and repair, which could then be utilized for viral DNA replication. Hence, while Brd4 can enhance replication by concentrating viral processes in specific regions of the host nucleus, this interaction is not absolutely essential for HPV replication.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Papillomaviruses have a remarkable infection cycle that depends on the development of a stratified epithelium. The virus infects the lower, dividing layers of the epithelium and viral genomes replicate at low copy number, and are maintained in these cells, for long periods of time. As infected cells differentiate and move to the surface of the epithelium, they switch on high level viral DNA replication, synthesize capsid proteins and form new viral particles. Viral replication takes place in nuclear foci and is dependent on the E1 and E2 replication proteins. Brd4 is a cellular chromatin binding protein that interacts with E2 and is important for transcriptional regulation of papillomaviruses. In this study we examine the role of Brd4 at different stages in the formation of viral replication foci. In the absence of viral DNA replication, Brd4 links the viral proteins to host chromatin. However, when viral genomes begin to amplify to high levels, Brd4 is displaced from nuclear foci and is not required for replication.</p>
</abstract>
<funding-group><funding-statement>This work was funded by the Intramural Research Program of the NIAID, and NIDDK, NIH. This work was also supported in part by NIH grant CA103867, CPRIT grant RP110471, and Welch Foundation grant I-1805 (to CMC).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><page-count count="23"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Maryland</li>
<li>Texas</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Maryland"><name sortKey="Sakakibara, Nozomi" sort="Sakakibara, Nozomi" uniqKey="Sakakibara N" first="Nozomi" last="Sakakibara">Nozomi Sakakibara</name>
</region>
<name sortKey="Chen, Dan" sort="Chen, Dan" uniqKey="Chen D" first="Dan" last="Chen">Dan Chen</name>
<name sortKey="Chiang, Cheng Ming" sort="Chiang, Cheng Ming" uniqKey="Chiang C" first="Cheng-Ming" last="Chiang">Cheng-Ming Chiang</name>
<name sortKey="Chiang, Cheng Ming" sort="Chiang, Cheng Ming" uniqKey="Chiang C" first="Cheng-Ming" last="Chiang">Cheng-Ming Chiang</name>
<name sortKey="Chiang, Cheng Ming" sort="Chiang, Cheng Ming" uniqKey="Chiang C" first="Cheng-Ming" last="Chiang">Cheng-Ming Chiang</name>
<name sortKey="Jang, Moon Kyoo" sort="Jang, Moon Kyoo" uniqKey="Jang M" first="Moon Kyoo" last="Jang">Moon Kyoo Jang</name>
<name sortKey="Kang, Dong Wook" sort="Kang, Dong Wook" uniqKey="Kang D" first="Dong Wook" last="Kang">Dong Wook Kang</name>
<name sortKey="Luecke, Hans F" sort="Luecke, Hans F" uniqKey="Luecke H" first="Hans F." last="Luecke">Hans F. Luecke</name>
<name sortKey="Mcbride, Alison A" sort="Mcbride, Alison A" uniqKey="Mcbride A" first="Alison A." last="Mcbride">Alison A. Mcbride</name>
<name sortKey="Wu, Shwu Yuan" sort="Wu, Shwu Yuan" uniqKey="Wu S" first="Shwu-Yuan" last="Wu">Shwu-Yuan Wu</name>
<name sortKey="Wu, Shwu Yuan" sort="Wu, Shwu Yuan" uniqKey="Wu S" first="Shwu-Yuan" last="Wu">Shwu-Yuan Wu</name>
</country>
</tree>
</affiliations>
</record>
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