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  • 1
    Publication Date: 2016-03-18
    Description: Chronic hepatitis B virus infection is a leading cause of cirrhosis and liver cancer. Hepatitis B virus encodes the regulatory HBx protein whose primary role is to promote transcription of the viral genome, which persists as an extrachromosomal DNA circle in infected cells. HBx accomplishes this task by an unusual mechanism, enhancing transcription only from extrachromosomal DNA templates. Here we show that HBx achieves this by hijacking the cellular DDB1-containing E3 ubiquitin ligase to target the 'structural maintenance of chromosomes' (Smc) complex Smc5/6 for degradation. Blocking this event inhibits the stimulatory effect of HBx both on extrachromosomal reporter genes and on hepatitis B virus transcription. Conversely, silencing the Smc5/6 complex enhances extrachromosomal reporter gene transcription in the absence of HBx, restores replication of an HBx-deficient hepatitis B virus, and rescues wild-type hepatitis B virus in a DDB1-knockdown background. The Smc5/6 complex associates with extrachromosomal reporters and the hepatitis B virus genome, suggesting a direct mechanism of transcriptional inhibition. These results uncover a novel role for the Smc5/6 complex as a restriction factor selectively blocking extrachromosomal DNA transcription. By destroying this complex, HBx relieves the inhibition to allow productive hepatitis B virus gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Decorsiere, Adrien -- Mueller, Henrik -- van Breugel, Pieter C -- Abdul, Fabien -- Gerossier, Laetitia -- Beran, Rudolf K -- Livingston, Christine M -- Niu, Congrong -- Fletcher, Simon P -- Hantz, Olivier -- Strubin, Michel -- England -- Nature. 2016 Mar 17;531(7594):386-9. doi: 10.1038/nature17170.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Medicine, University Medical Centre (C.M.U.), Rue Michel-Servet 1, 1211 Geneva 4, Switzerland. ; CRCL, INSERM U1052, CNRS 5286, Universite de Lyon, 151, Cours A Thomas, 69424 Lyon Cedex, France. ; Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; DNA, Viral/genetics/metabolism ; Genes, Reporter ; Genome, Viral/genetics ; Hepatitis B/virology ; Hepatitis B virus/genetics/*physiology ; Hepatocytes/virology ; *Host Specificity ; Humans ; Liver/metabolism/virology ; Male ; Mice ; Plasmids/genetics/metabolism ; Protein Binding ; Proteolysis ; Trans-Activators/*metabolism ; Transcription, Genetic ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-05-03
    Description: Transcription in eukaryotes is associated with two major changes in chromatin organization. Firstly, nucleosomal histones are continuously replaced by new histones, an event that in yeast occurs predominantly at transcriptionally active promoters. Secondly, histones become modified post-translationally at specific lysine residues. Some modifications, including histone H3 trimethylation at lysine 4 (H3K4me3) and acetylation at lysines 9 (H3K9ac) and 14 (H3K14ac), are specifically enriched at active promoters where histones exchange, suggesting a possible causal relationship. Other modifications accumulate within transcribed regions and one of them, H3K36me3, is thought to prevent histone exchange. Here we explored the relationship between these four H3 modifications and histone turnover at a few selected genes. Using lysine-to-arginine mutants and a histone exchange assay, we found that none of these modifications plays a major role in either promoting or preventing histone turnover. Unexpectedly, mutation of H3K56, whose acetylation occurs prior to chromatin incorporation, had an effect only when introduced into the nucleosomal histone. Furthermore, we used various genetic approaches to show that histone turnover can be experimentally altered with no major consequence on the H3 modifications tested. Together, these results suggest that transcription-associated histone turnover and H3 modification are two correlating but largely independent events.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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