Acetyltransferase Activity of TAF1 in Cell Cycle Gene Transcription

Acetyltransferase Activity of TAF1 in Cell Cycle Gene Transcription

The proper transcription of genes that control the cell division cycle is crucial for "normal" cell proliferation. Transcription is governed by the core machinery, which consists of the general transcription factors (TFIIA, B, D, E, F, and H) and the enzyme RNA polymerase II. The largest subunit of TFIID, TAF1, is unique in that it possesses histone acetyltransferase (HAT) activity, a function more commonly associated with regulatory protein complexes. The recruitment of HAT activity is well accepted as a mechanism for activating transcription by overcoming the repressive nature of genetic information packaged into chromatin. Although many genes that encode HATs are not essential for cell survival, mutations in TAF1 that disrupt its HAT activity induce cells to arrest in late G1 and eventually undergo apoptosis. Cells expressing TAF1 HAT mutants also display defects in the transcription of the cell cycle regulatory genes cyclin D1, E, and A. While much progress has been made towards understanding the function of histone acetylation in the transcription process, the significance of TAF1 acetyltransferase activity in the core transcription machinery remains to be determined.

We have results suggesting that acetylation of histone H3 by TAF1 is required for activation of cyclin D1 transcription. Some questions that we are specifically addressing include: "What defines the acetyltransferase domain of TAF1 and does it represent a distinct family of enzymes with unique regulatory properties? How does the interaction of TAF1 with TAF7 regulate TAF1 HAT activity and what are the effects of protein phosphorylation?" and "What are the signaling pathways that influence TAF1 HAT activity?" By elucidating the TAF1 dependent molecular mechanism regulating cyclin D1 transcription and carrying out structure-function studies on TAF1 HAT activity, our goal is to unveil new strategies for controlling the uninhibited proliferation of tumor cells and to determine if the acetyltransferase domain of TAF1 represents a potential therapeutic target for anti-cancer drugs.

Note: TAF1 was previously referred to as TAF250