p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus

Author:

Oikawa Tsukasa1ORCID,Hasegawa Junya2ORCID,Handa Haruka1,Ohnishi Naomi3,Onodera Yasuhito14,Hashimoto Ari1ORCID,Sasaki Junko2,Sasaki Takehiko2,Ueda Koji3,Sabe Hisataka15

Affiliation:

1. Department of Molecular Biology, Graduate School of Medicine, Hokkaido University

2. Department of Biochemical Pathophysiology/Lipid Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Japan

3. Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Koto-ku, Japan

4. Global Center for Biomedical Science and Engineering, Graduate School of Medicine, Hokkaido University

5. Institute for Genetic Medicine, Hokkaido University

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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

SGH Foundation

Tokyo Medical and Dental University

Publisher

Life Science Alliance, LLC

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