PDF(Pubmed)
Abstract：
H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here, we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 toward phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2.
摘要：
H3.1组蛋白主要是合成的，并在细胞周期的G1/S期进入细胞核，作为复制核小体的新成分。这里,我们发现p53对于确保G1/S阶段H3.1在细胞核中的正常行为和修饰是必需的，其中p53增加C末端结构域核包膜磷酸酶1（CTDNEP1）水平，并降低H3.1相互作用组中zeste同源物2（EZH2）的增强子水平。在没有p53的情况下，H3.1分子倾向于束缚在核膜（NE）处或附近，其中它们主要被EZH2在赖氨酸27（H3K27me3）处三甲基化，而不形成核小体。这种积累可能是由H3.1对磷脂酸（PA）的高亲和力引起的。p53通过增加CTDNEP1的水平来降低核PA水平,CTDNEP1激活脂素以将PA转化为二酰基甘油。我们还发现，胞浆H3分子伴侣HSC70减弱了H3.1-PA的相互作用，我们的分子成像分析表明，H3.1可能在核进入后锚定在NE周围。我们的结果扩展了我们对p53在G1/S期调节H3.1核行为中的功能的认识。其中p53可能主要靶向核PA和EZH2。
