p53 is remarkable in that wild type (WT) p53 is a crucial sentinel against cancer, but single amino acid substitutions within its DNA binding domain can cause loss of protective function and can transform p53, via gain-of-function (GOF) alterations, into a cancer-driving oncogene. Additionally, given that p53 inactivation is an essential step of oncogenesis, it is striking that many cancers maintain high levels of WT p53. Mechanisms underlying these complex functions of p53 have been investigated for decades, and yet mysteries persist about how a relatively small protein can encompass many distinct mechanisms and functions. Our previous epigenomic studies have begun to uncover modes of p53 interaction with chromatin, to explain WT and mtp53 activation of gene pathways. We helped to further define functional classes of the numerous p53 missense mutations. One mutant class loses direct DNA-binding activity, and instead is indirectly recruited to chromatin to drive expression of epigenetic genes. Another mutant class retains 50% of WT p53 DNA-binding affinity, however, whether these mtp53 retain binding in vivo, and how they drive cancer, is not understood. Finally, our previous findings showed that, in certain cancer cells bearing WT p53, methylation of the p53 protein (p53me) represses its normal tumor suppressive function, and preliminary findings point to a potential dominant oncogenic function of p53me. In the proposed studies we will address new mechanisms, gene targets, and potential therapeutics that are represented in these three major epigenetic pathways of p53 regulation. First, we will explore the oncogenic and genomic functions of ETS-dependent p53 GOF mutants. We will inhibit the interaction of mtp53 with ETS2, hypothesizing that that blocking the ETS2 interaction with GOF p53 is a promising strategy to selectively treat cancers harboring GOF p53 without disrupting WT p53. We will investigate the immediate transcriptional and chromatin consequences of mtp53 disruption, using a temperature-sensitive p53 mutant as well as rapid protein degradation systems. These approaches will advance fundamental understanding of mtp53?s molecular functions in the nucleus. Second, we will determine the oncogenic mechanisms of a direct- DNA binding class of p53 mutants. We propose a novel model of p53-mediated oncogenesis, whereby p53 mutants that retain intrinsic DNA-binding function at canonical p53 REs, also aberrantly activate cancer- related genes that neighbor tumor suppressor genes. We hypothesize that this ?gene target switching? involves mtp53 interacting with HMGA1 to facilitate new enhancer-promoter looping to cancer genes. Third, we will define roles of WT p53 in cancer. Our published results show p53me represses WT p53?s tumor suppressor activity, but the underlying mechanism mediating this repression is poorly understood. Further, we have evidence to suggest WT p53me may impart new oncogenic functions. We will test the hypothesis that WT p53me is utilized by cancer cells to not only repress canonical p53 activity but also to drive cancer growth.
p53, the most commonly mutated gene in human cancer, functions to activate gene expression and this mechanism is typically disrupted in tumors. Our work will elucidate normal and disease-altered mechanisms in gene regulatory and epigenetic pathways governed by p53. Our results will launch investigation of tailored epigenetic therapies to ameliorate specific p53-driven cancer phenotypes.
|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|
|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|
|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|
|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|
|Monteith, Jessica A; Mellert, Hestia; Sammons, Morgan A et al. (2016) A rare DNA contact mutation in cancer confers p53 gain-of-function and tumor cell survival via TNFAIP8 induction. Mol Oncol 10:1207-20|
|Dou, Zhixun; Ivanov, Andrejs; Adams, Peter D et al. (2016) Mammalian autophagy degrades nuclear constituents in response to tumorigenic stress. Autophagy 12:1416-7|
Showing the most recent 10 out of 24 publications