Abstract
The Ski-interacting protein SKIP/SNW1 associates with the P-TEFb/CDK9 elongation factor and coactivates inducible genes, including HIV-1. We show here that SKIP also associates with c-Myc and Menin, a subunit of the MLL1 histone methyltransferase (H3K4me3) complex and that HIV-1 Tat transactivation requires c-Myc and Menin, but not MLL1 or H3K4me3. RNAi-ChIP experiments reveal that SKIP acts downstream of Tat:P-TEFb to recruit c-Myc and its partner TRRAP, a scaffold for histone acetyltransferases, to the HIV-1 promoter. By contrast, SKIP is recruited by the RNF20 H2B ubiquitin ligase to the basal HIV-1 promoter in a step that is bypassed by Tat and downregulated by c-Myc. Of interest, we find that SKIP and P-TEFb are dispensable for UV stress-induced HIV-1 transcription, which is strongly upregulated by treating cells with the CDK9 inhibitor flavopiridol. Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an elongation step that is bypassed under stress.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Cyclin T / genetics
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Cyclin T / metabolism
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / metabolism
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DNA Damage / physiology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Flavonoids / pharmacology
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Gene Expression Regulation, Viral / drug effects
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Gene Expression Regulation, Viral / physiology*
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Gene Expression Regulation, Viral / radiation effects
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HIV Long Terminal Repeat / physiology
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HeLa Cells
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Histone-Lysine N-Methyltransferase
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Histones / metabolism
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Humans
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Methylation
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Coactivators / genetics
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Nuclear Receptor Coactivators / metabolism*
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Piperidines / pharmacology
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Positive Transcriptional Elongation Factor B / antagonists & inhibitors
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Positive Transcriptional Elongation Factor B / metabolism
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Promoter Regions, Genetic / physiology
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA, Small Interfering / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology*
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Transcriptional Activation / radiation effects
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Ubiquitin-Protein Ligases / genetics
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Ultraviolet Rays
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tat Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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ASH2L protein, human
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Adaptor Proteins, Signal Transducing
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CCNT1 protein, human
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Cyclin T
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DNA-Binding Proteins
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Flavonoids
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Histones
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KMT2A protein, human
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MEN1 protein, human
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Nuclear Proteins
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Nuclear Receptor Coactivators
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Piperidines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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SNW1 protein, human
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Transcription Factors
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tat Gene Products, Human Immunodeficiency Virus
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transformation-transcription domain-associated protein
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Myeloid-Lymphoid Leukemia Protein
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alvocidib
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Histone-Lysine N-Methyltransferase
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RNF20 protein, human
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Ubiquitin-Protein Ligases
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Positive Transcriptional Elongation Factor B
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CDK9 protein, human
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Cyclin-Dependent Kinase 9