p53 controls the nuclear entry and epigenetic modification of H3.1 by downregulating nuclear phosphatidic acid

Abstract

AbstractH3.1 is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, although the underlying mechanism remains unknown. Here we show that p53 is involved in this process. CTDNEP1 converts phosphatidic acid (PA) into diacylglycerol, and EZH2 generates H3K27me3. p53 increased CTDNEP1 and decreased EZH2 in the nuclear H3.1 interactome of the G1/S phase. Moreover, H3.1 bound robustly to PA but not to diacylglycerol. p53 deficiency caused perinuclear accumulation of EZH2-modified H3K27me3 of non-nucleosomal histones during the G1/S phase. p53 induced the expression ofTMEM255A, which reduced nuclear PA levels by increasing CTDNEP1 levels. Therefore, H3.1 entering the nucleus in the absence of p53 may be trapped near the nuclear envelope (NE) and epigenetically marked as repressive without forming nucleosomes. Our study identified the NE as a novel target of p53, in which p53 downregulates nuclear PA levels to normalize H3.1 nuclear entry and epigenetic modification.