The SANT domain of p400 ATPase represses acetyltransferase activity and coactivator function of TIP60 in basal p21 gene expression.
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.
Park
Jeong Hyeon
JH
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Sun
Xiao-Jian
XJ
Roeder
Robert G
RG
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D000251:Adenosine Triphosphatases; C119652:SRCAP protein, human