title: Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA.
abstract: Adenoviruses are linear double-stranded DNA viruses that infect human and rodent cell lines, occasionally transform them and cause tumors in animal models. The host cell challenges the virus in multifaceted ways to restrain viral gene expression and DNA replication, and sometimes even eliminates the infected cells by programmed cell death. To combat these challenges, adenoviruses abrogate the cellular DNA damage response pathway. Tip60 is a lysine acetyltransferase that acetylates histones and other proteins to regulate gene expression, DNA damage response, apoptosis and cell cycle regulation. Tip60 is a bona fide tumor suppressor as mice that are haploid for Tip60 are predisposed to tumors. We have discovered that Tip60 is degraded by adenovirus oncoproteins EIB55K and E4orf6 by a proteasome-mediated pathway. Tip60 binds to the immediate early adenovirus promoter and suppresses adenovirus EIA gene expression, which is a master regulator of adenovirus transcription, at least partly through retention of the virally encoded repressor pVII on this promoter. Thus, degradation of Tip60 by the adenoviral early proteins is important for efficient viral early gene transcription and for changes in expression of cellular genes.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, VA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: S
authors.initials: S
authors.lastname: Jha
authors.forename: D A
authors.initials: DA
authors.lastname: Engel
authors.forename: D A
authors.initials: DA
authors.lastname: Ornelles
authors.forename: A
authors.initials: A
authors.lastname: Dutta
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line / Q000821:virology; D004279:DNA, Viral / Q000096:biosynthesis; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells / Q000187:drug effects / Q000821:virology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic; D061988:Proteasome Inhibitors / Q000494:pharmacology
chemical_list: D017500:Adenovirus E1A Proteins; D017504:Adenovirus E4 Proteins; D004279:DNA, Viral; C553318:E4orf6 protein, adenovirus; D007976:Leupeptins; D061988:Proteasome Inhibitors; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde