Inhibition of transcription and DNA replication by the papillomavirus E8-E2C protein is mediated by interaction with corepressor molecules.
Papillomavirus genomes replicate as nuclear plasmids at a low copy number in undifferentiated keratinocytes. Papillomaviruses encode the E1 and E2 proteins that bind to the origin of replication and are required for the activation of replication. In addition to E2, several papillomaviruses express an E8-E2C protein, which is generated by alternative splicing and functions as a transcriptional repressor and inhibitor of the E1/E2-dependent replication of the viral origin. Previous analyses suggested that the E8 domain functions as a transferable repression domain. In this report we present evidence that the E8 domain is responsible for the interaction with cellular corepressor molecules such as histone deacetylases, the histone methyltransferase SETDB1, and the TRIM28/KAP-1/TIF1beta/KRIP-1 protein. Whereas the interaction with histone deacetylases is involved only in transcriptional repression, the interaction with TRIM28/KAP-1/TIF1beta/KRIP-1 contributes to the inhibition of E1/E2-dependent replication. The corepressor TRIM28/KAP-1/TIF1beta/KRIP-1 has been described to be part of multicomponent complexes involved in transcriptional regulation and functions as a scaffold protein. Since neither histone deacetylases nor the histone methyltransferase SETDB1 appears to be involved in the inhibition of E1/E2-dependent replication, most likely the modification of non-histone proteins contributes to the replication repression activity of E8-E2C.
Ammermann
Ingo
I
Sektion Experimentelle Virologie, Institut fuer Medizinische Virologie und Epidemiologie der Viruskrankheiten, Universitaetsklinikum Tuebingen, Elfriede Aulhorn Str. 6, D72076 Tuebingen, Germany.
Bruckner
Markus
M
Matthes
Frank
F
Iftner
Thomas
T
Stubenrauch
Frank
F
D000818:Animals; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification / Q000378:metabolism; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism; D018741:Replication Origin / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
D056572:Histone Deacetylase Inhibitors; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D011496:Protein Methyltransferases; D006655:Histone Deacetylases