The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to DNA damage. Recent studies from several laboratories, including our own, suggest that the full transcriptional activity of p53 requires the transcriptional coactivator proteins CBP and PCAF. These two coactivators, and their yeast homologues ADA2 and GCN5, have acetyltransferase activity. The nucleosomes are generally considered to be the target of this acetylase activity; however, recent results suggest that CBP can also acetylate p53 and in doing so modulate its sequence-specific DNA binding activity. We have been investigating the role of coactivator acetyltransferase activity on gene transcription in yeast and mammalian cells. The GCN5 coactivator has been subjected to extensive mutagenesis analysis and a close link between acetyltransferase activity and coactivator function has been established. We have also been studying the transactivation domain of the p53 tumor suppressor protein and mapped the residues within this domain that are critical for function. We have established that there is a physical interaction between p53 and CBP and that the transcriptional activity of p53 requires both CBP and PCAF. Furthermore, we show that PCAF acetylates p53 in vitro and does so at a specific lysine distinct from that acetylated by CBP. We propose here to study the role of the acetyltransferase activity of PCAF on the transcriptional activity of p53. Our hypothesis considers that CBP and PCAF together as a complex acetylate both nucleosomes and p53 and that both targets are critical for the full transcriptional activity of p53. Our research design will probe the acetylation state of nucleosomes and p53 and utilize both cell-free (in vitro) and tissue culture (in vivo) assays of p53 function to elucidate the role of such acetylation. The long term goal of our studies is to elucidate the molecular mechanism by which coactivators function to induce the transcriptional and tumor suppressor function of p53.
| Lin-Shiao, Enrique; Lan, Yemin; Coradin, Mariel et al. (2018) KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes Dev 32:181-193 |
| Dou, Zhixun; Berger, Shelley L (2018) Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse. Cell Metab 27:710-711 |
| Bose, Daniel A; Donahue, Greg; Reinberg, Danny et al. (2017) RNA Binding to CBP Stimulates Histone Acetylation and Transcription. Cell 168:135-149.e22 |
| Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4 |
| Dou, Zhixun; Ghosh, Kanad; Vizioli, Maria Grazia et al. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406 |
| Levine, Arnold J; Berger, Shelley L (2017) The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev 31:1195-1201 |
| Bose, Daniel A; Berger, Shelley L (2017) eRNA binding produces tailored CBP activity profiles to regulate gene expression. RNA Biol 14:1655-1659 |
| Pauken, Kristen E; Sammons, Morgan A; Odorizzi, Pamela M et al. (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160-1165 |
| Zhu, Jiajun; Dou, Zhixun; Sammons, Morgan A et al. (2016) Lysine methylation represses p53 activity in teratocarcinoma cancer cells. Proc Natl Acad Sci U S A 113:9822-7 |
| Sammons, Morgan A; Zhu, Jiajun; Berger, Shelley L (2016) A Chromatin-Focused siRNA Screen for Regulators of p53-Dependent Transcription. G3 (Bethesda) 6:2671-8 |
Showing the most recent 10 out of 24 publications
