Molecular mechanism of the p53-mediated intra-nuclear dynamics of H3K27me3

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07305
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Hokkaido University
• Principal Investigator: Oikawa Tsukasa 北海道大学, 医学研究院, 講師 (20457055)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: H3.1 / p53 / H3K27me3

Outline of Final Research Achievements

H3.1 is a DNA replication-dependent histone, predominantly synthesized and enters into the nucleus during S phase of the cell cycle. Although molecular chaperones that guide H3.1 to sites of the DNA replication are identified, processes related to the H3.1 nuclear entry remain largely unknown. We showed that p53 is involved therein. C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) was found within the H3.1 interactome. CTDNEP1 is known to convert phosphatidic acid (PA) to diacylglycerol (DAG) via lipin PA phosphatases, and we found that H3.1 exhibits a significantly higher affinity to PA than to DAG. Loss of p53 increased nuclear PA levels, in which CTDNEP1 levels were downregulated. Intriguingly, H3.1 molecules, not yet interacting with DNA, were accumulated in the vicinity of the nuclear envelope (NE) and K27-trimethylated perhaps by EZH2. These events were predominantly observed during the S phase.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

p53は上皮細胞の分化形質の維持において重要な働きをする。その機構として、p53が発現誘導するmicro RNAsを介し、上皮間葉転換に関連した遺伝子発現変化を引き起こす転写因子(ZEB1, SNAI1など)の発現が抑制されることが重要であるとされてきた。しかし、p53喪失は上皮性を失わせる場合がある一方、そうでない場合もある。さらに、線維芽細胞などの間葉系細胞においてもp53は発現しているが、ZEB1等が常に発現し、上皮性は認められない。従って、細胞の分化形質維持におけるp53機能について我々の理解は十分とは言えず、本研究による成果はこの点で我々の理解を拡大するものである。