The Functional Study On Histone Methyltransferase SETD2 Regulating The Transcriptional Activity Of P53

p53 is a transcriptional factor that has a pivotal role in controlling the cell cycle, apoptosis and DNA repair in response to various genotoxic stresses.The steady-state levels and transcriptional activity of p53 increase dramatically in cells that sustain various types of stresses. In addition, many tumors retaining wide-type p53 often have defects in activating or responding to p53. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through post-translation modifications of p53. The number and types of different post-translational modifications can contribute to its stabilization and activation. Recent study showed that p53 can also be modified by histone methyltransferase SET8, SET9 and SmyD2, which was a brand-new kind of modification for p53. It is well accepted that the methylation pathway may plays a major part in the scope of p53 regulation.Human SETD2 is a member of the SET domain-containing methyltransferase family that can specifically methylate histone H3 at lysine 36. SETD2 associates with hyperphosphorylated RNA polymerase II (RNAPII) which impacts transcription control. However, whether and how SETD2 is implicated in the specific regulation of gene transcription remains unclear. Here we show that SETD2 could interact with p53 and selectively regulate the transcription factor activity of p53. The interaction was dependent of C terminal region of SETD2, which contains the SET and WW domains, and the N-terminal transactivation domain (residues 1-45) of p53. Overexpression of SETD2 upregulated the expression levels of a subset of p53 targets including puma, noxa, p53AIP1, fas, p21, tsp1, huntingtin, but downregulated that of hdm2. In contrast, it had no significant effect on those of 14-3-3σ, gadd45 and pig3. Consistently, knock-down of endogenous SETD2 expression by RNA interference resulted in converse effects as expected. In p53-deficient H1299 cells, SETD2 lost the ability to regulate these gene expression except hdm2, indicating the dependence of p53. Furthermore, we demonstrated that SETD2 downregulated hdm2 expression by targeting its P2 promoter and then enhanced p53 protein stability. Collectively, these findings suggest that the histone methyltransferase SETD2 could selectively regulate the transcription of subset genes via cooperation with the transcription factor p53.