Abstract
Master regulator protein p53, popularly known as the “guardian of genome” is the hub for regulation of diverse cellular pathways. Depending on the cell type and severity of DNA damage, p53 protein mediates cell cycle arrest or apoptosis, besides activating DNA repair, which is apparently achieved by regulation of its target genes, as well as direct interaction with other proteins. p53 is known to repress target genes via multiple mechanisms one of which is via recruitment of chromatin remodelling Sin3/HDAC1/2 complex. Sin3 proteins (Sin3A and Sin3B) regulate gene expression at the chromatin-level by serving as an anchor onto which the core Sin3/HDAC complex is assembled. The Sin3/HDAC co-repressor complex can be recruited by a large number of DNA-binding transcription factors. Sin3A has been closely linked to p53 while Sin3B is considered to be a close associate of E2Fs. The theme of this study was to establish the role of Sin3B in p53-mediated gene repression. We demonstrate a direct protein-protein interaction between human p53 and Sin3B (hSin3B). Amino acids 1–399 of hSin3B protein are involved in its interaction with N-terminal region (amino acids 1–108) of p53. Genotoxic stress induced by Adriamycin treatment increases the levels of hSin3B that is recruited to the promoters of p53-target genes (HSPA8, MAD1 and CRYZ). More importantly recruitment of hSin3B and repression of the three p53-target promoters upon Adriamycin treatment were observed only in p53+/+ cell lines. Additionally an increased tri-methylation of the H3K9 residue at the promoters of HSPA8 and CRYZ was also observed following Adriamycin treatment. The present study highlights for the first time the essential role of Sin3B as an important associate of p53 in mediating the cellular responses to stress and in the transcriptional repression of genes encoding for heat shock proteins or proteins involved in regulation of cell cycle and apoptosis.
Highlights
The p53 gene is widely recognized as the master regulator of diverse cellular networks. p53 is a sequence specific transcription factor capable of transactivation and transrepression [1,2,3]
Since we observed an interaction between p53 and human p53 and Sin3B (hSin3B), we investigated the changes in the RNA and protein levels of hSin3B upon treatment with Adriamycin, a DNA damaging agent known to increases the levels of p53 and elicit a p53 response [22,23,24]
We investigated the effect of Adriamycin treatment on the mRNA levels of HSPA8, Mitotic arrest deficientlike 1 protein (MAD1) and CRYZ genes
Summary
The p53 gene is widely recognized as the master regulator of diverse cellular networks. p53 is a sequence specific transcription factor capable of transactivation and transrepression [1,2,3]. The last decade, has witnessed identification of principally three mechanisms for repression of a repertoire of p53 target genes: competition with transcription activator for DNA binding, sequestration of transcription activators or recruitment of corepressor/chromatin-modifying factors Recruitment of co-repressor complex like Sin3/HDAC complex by DNA binding transcription factor is an evolutionary conserved mechanism of transrepression. Sin3A is involved in mediating p53 dependent gene repression [6,8], while Sin3B/ HDAC co-repressor complex is recognized to be an essential regulator of chromatin modification at the E2F-target promoters We demonstrate recruitment of the human Sin3B/ HDAC1 complex at three of the p53-repressed target promoters accompanied by altered histone methylation and a concomitant repression of these genes under conditions of genotoxic insult, thereby highlighting for the first time, Sin3B as an important player in p53-mediated gene repression
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