Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
Nucleic Acids Res. 2022 May 6;50(8):4500-4514. doi: 10.1093/nar/gkac259.
Histone H3.3 is an H3 variant which differs from the canonical H3.1/2 at four residues, including a serine residue at position 31 which is evolutionarily conserved. The H3.3 S31 residue is phosphorylated (H3.3 S31Ph) at heterochromatin regions including telomeres and pericentric repeats. However, the role of H3.3 S31Ph in these regions remains unknown. In this study, we find that H3.3 S31Ph regulates heterochromatin accessibility at telomeres during replication through regulation of H3K9/K36 histone demethylase KDM4B. In mouse embryonic stem (ES) cells, substitution of S31 with an alanine residue (H3.3 A31 -phosphorylation null mutant) results in increased KDM4B activity that removes H3K9me3 from telomeres. In contrast, substitution with a glutamic acid (H3.3 E31, mimics S31 phosphorylation) inhibits KDM4B, leading to increased H3K9me3 and DNA damage at telomeres. H3.3 E31 expression also increases damage at other heterochromatin regions including the pericentric heterochromatin and Y chromosome-specific satellite DNA repeats. We propose that H3.3 S31Ph regulation of KDM4B is required to control heterochromatin accessibility of repetitive DNA and preserve chromatin integrity.
组蛋白 H3.3 是一种 H3 变体，与经典的 H3.1/2 在四个残基上不同，包括位于第 31 位的丝氨酸残基，该残基在进化上是保守的。H3.3 的 S31 残基在包括端粒和着丝粒重复序列在内的异染色质区域发生磷酸化（H3.3 S31Ph）。然而，H3.3 S31Ph 在这些区域的作用仍然未知。在这项研究中，我们发现 H3.3 S31Ph 通过调节 H3K9/K36 组蛋白去甲基化酶 KDM4B 来调节复制过程中端粒处异染色质的可及性。在小鼠胚胎干细胞（ES）中，用丙氨酸取代 S31（H3.3 A31-磷酸化无效突变体）会导致 KDM4B 活性增加，从而从端粒上去除 H3K9me3。相比之下，用谷氨酸取代 S31（H3.3 E31，模拟 S31 磷酸化）会抑制 KDM4B，导致端粒处 H3K9me3 和 DNA 损伤增加。H3.3 E31 的表达也会增加其他异染色质区域的损伤，包括着丝粒异染色质和 Y 染色体特异性卫星 DNA 重复序列。我们提出，H3.3 S31Ph 对 KDM4B 的调节对于控制重复 DNA 的异染色质可及性和维持染色质完整性是必需的。
