The human proliferating Cell nuclear antigen regulates transcriptional coactivator p300 activity and promotes transcriptional repression.
Chromatin structure plays an important role in DNA replication, repair, and transcription. p300 is a transcriptional coactivator with protein acetyltransferase activity, and proliferating cell nuclear antigen (PCNA) plays important roles in DNA replication and repair. It has been shown recently that p300 is necessary for DNA synthesis and repair. However, it is not known whether human PCNA, in a reciprocal manner, can regulate the enzymatic activity and transcriptional regulatory properties of p300. Here we show that human PCNA associates with p300 and potently inhibits the acetyltransferase activity and transcriptional activation properties of p300. Surprisingly, PCNA fails to inhibit p300/CBP-associated factor (PCAF) acetyltransferase function as well as PCAF-dependent transcription. Additionally, PCNA potently represses transcription when targeted to chromatin in vivo. Consistent with these observations, using chromatin immunoprecipitation assays, we demonstrate that PCNA recruitment to promoters causes hypoacetylation of chromatin. Together, our results demonstrate for the first time a novel role for human PCNA in transcriptional repression and in modulating chromatin modification. The reciprocal modulation of p300 and PCNA activities by each other provides an example of integrative regulatory cross-talk among chromatin-based processes such as DNA transcription, repair, and synthesis.
Hong
Rui
R
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
Chakravarti
Debabrata
D
D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007163:Immunosorbent Techniques; D051379:Mice; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D002843:Chromatin; D004247:DNA; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; D051548:Histone Acetyltransferases; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor