The Barlev Laboratory focuses on the role of post-translational modifications in regulation of transcriptional programs mediated by tumor suppressor genes, in particular p53. The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to genotoxic stress, including DNA damage. Upon activation, p53 undergoes massive post-translational modifications that ultimately regulate its biological function. We have demonstrated previously that acetylation of p53 stimulates recruitment of CBP to the target promoters resulting in acetylation of histones and activation of transcription.

Currently, we are studying p53 methylation by histone methyltransferase Set9. Based on the methylation analysis of histones, we predict that this modification will be also important for the regulation of p53 function. The overall working hypothesis is that methylation regulates p53 at multiple levels: at the level of transcription of the p53-dependent genes and p53 by itself (histone methylation); and at the level of protein-protein interactions (p53 methylation). Upon DNA damage, p53 recruits both histone acetyltransferases (HATs) and histone methyltransferases (HMTases). This event causes acetylation and methylation of both histones and p53 by itself, facilitating the conversion of the chromatin structure in the promoters of p53-activated genes from a transcriptionally repressive into a transcriptionally active state. The latter event will ultimately result in activation of transcription. The long-term goal of our studies is to elucidate the role of post-translational modifications of p53 and chromatin in respect to the transcriptional and tumor suppressor function of p53. We are also planning to expand our methylation studies on other tumor suppressors.