For proper cellular function and the elaboration of developmental programs, transcription factors, and the protein complexes needed for DNA replication and repair must gain access to the DNA that is packaged into chromatin. Recent work has found connections between the protein complexes that initiate transcription and those that modify chromatin structure. For example the SWI/SNF and Brahma class of proteins are thought to remodel chromatin in an ATP-dependent fashion and thus to facilitate the initiation of transcription. Alternate strategies involve the post-translational modification of the histones by acetyltransferases like GCN5, CBP, TAFII250 and SRC-1 that opens the nucleosome to transcription complexes. Our goal is to understand how the histone acetyltransferase (HAT) activity of the signal-responsive co-activator CBP affects its ability to transactivate and remodel chromatin and whether this activity is required for all of CBP function. We have evidence to suggest that the Drosophila homologue of CBP, dCBP, can affect silencing near heterochromatin and thus may modulate higher order chromatin structure.
The aims outlined in this proposal will test the hypothesis that dCBP function in Drosophila development is dependent upon HAT activity and define the targets of dCBP HAT activity. Finally, we will determine whether dCBP can modify higher-order chromatin structure in Drosophila, whether this function depends upon HAT activity and define proteins that may function with dCBP in regulating heterochromatin. One of the main advantages of using Drosophila for these studies is that there are so many examples of chromatin or nuclear architecture affecting gene expression that have been genetically defined. In this proposal we will use a few of these systems in an effort to understand how transcriptional co-activators affect gene expression through the remodeling of chromatin structure.
| Smolik, Sarah M (2009) Heterochromatin-mediated gene silencing is not affected by Drosophila CBP activity. J Hered 100:465-72 |
| Smolik, Sarah; Jones, Kristen (2007) Drosophila dCBP is involved in establishing the DNA replication checkpoint. Mol Cell Biol 27:135-46 |
