Abstract 748: Studying the significance of human p53-Sin3B interaction under the condition of DNA damage.

Abstract

Abstract Sin3, a global regulator of transcription plays an important role in mediating gene regulation, by binding to various transcription factors through its highly conserved Paired Amphipathic Helices (PAH) domains. Physical association of Sin3 corepressor molecule with human p53, a tumour suppressor protein is now well established. In response to stimuli that activate p53, cells can undergo repair processes, cell cycle arrest or apoptosis. In order to combat the stress, p53 gets activated by posttranslational stabilization and modulate the expression levels of its target genes. There are number of genes which are negatively regulated by p53, but the mechanism of repression is not well characterized. We hereby show that p53 interacts with Sin3/HDAC corepressor complex in-vivo and expression of Sin3B is up regulated in response to DNA damaging stimuli in p53 dependent manner. Increase in the levels of Sin3B upon different kind of DNA damage suggests that Sin3B might be an important protein involved in DNA damage pathway. Sin3/HDAC corepressor complex is recruited by p53 onto the promoters of its target genes, resulting in the down regulation of p53 target genes. In our study we propose that the mechanism of repression of p53 target genes is through recruitment of Sin3/HDAC corepressor complex which leads to context specific chromatin modification. Such modifications results in enrichment of epigenetic marks like H3K9me3, H3K27me3, which are marker of repression under condition of DNA damage induced by Bleomycin. Knockdown of Sin3B using shRNA causes derepression of p53 target genes, suggesting that Sin3B is a key player in p53 mediated transrepression. Based on our studies we propose that Sin3B is an important corepressor molecule recruited by p53 in response to DNA damage and Increased Sin3B expression is an early event in DNA damage induced by Bleomycin. We further provide evidence that p53 regulate its target genes, namely HSPA8, MAD1, CRYZ, ANLN and CDC25c through its interaction with Sin3/HDAC corepressor complex which leads to chromatin modification by recruiting proteins involved in epigenetic modifications. Citation Format: Rama Kadamb, Shilpi Mittal, Nidhi Bansal, Bilikere Srinivasa Rao Dwarakanath, Daman Saluja. Studying the significance of human p53-Sin3B interaction under the condition of DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 748. doi:10.1158/1538-7445.AM2013-748