Turnell et al. report cell cycle-independent interaction between the anaphase-promoting complex/cyclosome (APC/C) and the histone acetyltransferase transcriptional coactivators CBP and p300 (CBP/p300). This interaction was mediated by the APC5 and APC7 subunits, which have a domain similar to the viral protein EA1 N-terminal CR1 region that is known to interact with CBP/p300. APC5 and APC7 increased CBP/p300-mediated gene expression in two reporter assays. APC subunits (APC5 and APC7, as well as subunits that did not directly bind CBP/p300) were detected by chromatin immunoprecipitation at two CBP/p300-regulated genes: p21CIP/WAF1 and cdc6. In vitro assays indicated that APC/C enhanced p300 acetyltransferase activity. RNAi-mediated inhibition of APC5 or APC7 decreased p53-mediated stimulation of p21CIP/WAF1 gene expression and protein abundance in response to ionizing radiation without decreasing the abundance of p53. In cells in which APC5 or APC7 was knocked down, acetylated histone 4 (H4) at the p21CIP/WAF1 and the cdc6 promoter was decreased, as was the acetylation of p300 itself. The abundance of CBP and p300 was increased in cells deficient for APC5 or APC7. Thus, APC/C appears both to control the abundance of CBP/p300 and to stimulate the acetyltransferase activity of the protein. Reciprocal regulation of APC/C was also noted, such that CBP and p300 immunoprecipitates exhibited ubiquitin ligase activity. Cells in which CBP was knocked down, but not those in which p300 was knocked down, exhibited decreased APC/C ubiquitin ligase activity, increased abundance of APC/C substrates, and accumulation of cells in mitosis. CBP and APC/C colocalized during mitosis. Thus, APC/C and CBP/p300 appear to directly regulate each other's enzymatic activity, allowing APC/C to contribute to cell cycle-independent gene regulation and CBP to contribute to cell cycle progression.
A. S. Turnell, G. S. Stewart, R. J. A. Grand, S. M. Rookes, A. Martin, H. Yamano, S. J. Elledge, P. H. Gallimore, The APC/C and CBP/p300 cooperate to regulate transcription and cell cycle progression. Nature 438, 690-695 (2005). [PubMed]