The SANT Domain of p400 ATPase Represses Acetyltransferase Activity and Coactivator Function of TIP60 in Basal p21 Gene Expression

Abstract

The TIP60 histone acetyltransferase plays diverse roles in DNA damage responses, DNA double-strand break repair, and transcriptional regulation. TIP60 resides within a multisubunit complex that has been shown to be targeted by transcription factors and to be involved in histone acetylation and transcriptional activation. p400, an SWI2/SNF2-related ATPase that serves as an ATP-dependent chromatin remodeling enzyme, exists as an integral subunit of a TIP60 complex but also resides within a distinct complex that presumably lacks TIP60 and appears to be involved in the transcriptional repression of basal p53 target gene expression. Here, we describe a TIP60-containing p400 complex population in which the acetyltransferase activity of TIP60 is repressed by interactions with p400. We further show that an SWI3-ADA2-N-CoR-TFIIIB (SANT) domain of p400 binds directly to the histone acetyltransferase (HAT) domain of TIP60 and blocks both its enzymatic activity and its coactivator function in regulating basal p21 gene expression. Our results thus suggest that p400 represses basal p21 gene expression through dual mechanisms that include the direct inhibition of TIP60 enzymatic activity described here and the previously described ATP-dependent positioning of H2A.Z at the promoter.

We thank Janice Ascano for critical reading of the manuscript, members of Roeder laboratory for fruitful discussions, Wei-Yi Chen for human H2A.Z cDNA, Jaehoon Kim for advice on baculovirus construction, and Michael Cole for CβS expression vectors.

This work was supported by grants from the NIH (CA129325 and DK071900), the Leukemia and Lymphoma Society (SCOR grant 7132-08), and the Starr Cancer Consortium (I2-A88) to R.G.R. and by a MURF grant to J.H.P.