Apoptotic Phosphorylation of Histone H3 on Ser-10 by Protein Kinase Cδ

Phosphorylation of histone H3 on Ser-10 is regarded as an epigenetic mitotic marker and is tightly correlated with chromosome condensation during both mitosis and meiosis. However, it was also reported that histone H3 Ser-10 phosphorylation occurs when cells are exposed to various death stimuli, suggesting a potential role in the regulation of apoptosis. Here we report that histone H3 Ser-10 phosphorylation is mediated by the pro-apoptotic kinase protein kinase C (PKC) δ during apoptosis. We observed that PKCδ robustly phosphorylates histone H3 on Ser-10 both in vitro and in vivo. Ectopic expression of catalytically active PKCδ efficiently induces condensed chromatin structure in the nucleus. We also discovered that activation of PKCδ is required for histone H3 Ser-10 phosphorylation after treatment with DNA damaging agents during apoptosis. Collectively, these findings suggest that PKCδ is the kinase responsible for histone H3 Ser-10 phosphoryation during apoptosis and thus contributes to chromatin condensation together with other apoptosis-related histone modifications. As a result, histone H3 Ser-10 phosphorylation can be designated a new ‘apoptotic histone code’ mediated by PKCδ.

组蛋白H3丝氨酸10位点的磷酸化被视为表观遗传有丝分裂标记物，且在有丝分裂与减数分裂过程中均与染色体凝缩紧密相关。然而已有研究表明，当细胞暴露于多种死亡刺激时，亦会发生组蛋白H3丝氨酸10位点的磷酸化，提示其在细胞凋亡调控中存在潜在功能。本研究证实，细胞凋亡过程中组蛋白H3丝氨酸10位点的磷酸化由促凋亡激酶蛋白激酶C（PKC）δ介导。研究团队观察到，PKCδ可在体外与体内环境中高效催化组蛋白H3丝氨酸10位点的磷酸化。异位表达具有催化活性的PKCδ，可有效诱导细胞核内染色质凝缩结构的形成。本研究同时发现，在细胞凋亡阶段经DNA损伤剂处理后，PKCδ的激活是组蛋白H3丝氨酸10位点磷酸化的必要条件。综上，上述研究结果表明，PKCδ是细胞凋亡过程中催化组蛋白H3丝氨酸10位点磷酸化的激酶，并可与其他凋亡相关组蛋白修饰协同参与染色质凝缩过程。据此，组蛋白H3丝氨酸10位点的磷酸化可被定义为由PKCδ介导的新型‘凋亡组蛋白密码’。