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The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc
S B McMahon1, M A Wood, M D Cole
1Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA.
Abstract:
The c-Myc protein functions as a transcription factor to facilitate oncogenic transformation; however, the biochemical and genetic pathways leading to transformation remain undefined. We demonstrate here that the recently described c-Myc cofactor TRRAP recruits histone acetylase activity, which is catalyzed by the human GCN5 protein. Since c-Myc function is inhibited by recruitment of histone deacetylase activity through Mad family proteins, these opposing biochemical activities are likely to be responsible for the antagonistic biological effects of c-Myc and Mad on target genes and ultimately on cellular transformation.
Insights
The c-Myc cofactor TRRAP recruits histone acetylase activity via human GCN5, opposing Mad proteins' deacetylase activity. This balance regulates oncogenic transformation and target gene expression.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- The c-Myc oncoprotein is a transcription factor driving oncogenic transformation.
- The precise biochemical and genetic mechanisms underlying c-Myc-induced transformation are not fully understood.
Purpose of the Study:
- To elucidate the biochemical pathways involving c-Myc in cellular transformation.
- To investigate the role of the c-Myc cofactor TRRAP and associated enzymatic activities.
Main Methods:
- Investigated the interaction between c-Myc cofactor TRRAP and histone acetylase activity.
- Examined the catalytic role of human GCN5 protein in this complex.
- Compared the effects of histone acetylase recruitment by c-Myc/TRRAP with histone deacetylase recruitment by Mad proteins.
Main Results:
- Demonstrated that TRRAP recruits histone acetylase activity, catalyzed by human GCN5.
- Showed that c-Myc function is inhibited by Mad protein-mediated histone deacetylase recruitment.
- Identified opposing enzymatic activities regulating c-Myc and Mad functions on target genes.
Conclusions:
- The balance between histone acetylation (via c-Myc/TRRAP/GCN5) and deacetylation (via Mad proteins) is crucial.
- These opposing epigenetic modifications likely mediate the antagonistic effects of c-Myc and Mad on gene expression.
- This regulatory mechanism is fundamental to controlling cellular transformation.