Phosphorylation of Histone H3 Thr-45 Is Linked to Apoptosis
Phosphorylation of Histone H3 Thr-45 Is Linked to Apoptosis
复制标题
DOI：
10.1074/jbc.m109.005421
复制
发表时间：
2009-06-12
影响因子：
4.8
通讯作者：
Kouzarides, Tony
中科院分区：
文献类型：
--
作者：
Hurd, Paul J.;Bannister, Andrew J.;Kouzarides, Tony
在组蛋白中已经鉴定出许多翻译后修饰。大多数发生在组蛋白尾部，但也有一些在组蛋白核心序列中被发现。组蛋白核心翻译后修饰具有直接调节核小体结构和DNA可及性的潜力。在这里，我们确定组蛋白H3（H3 T45）的苏氨酸45作为在体内的磷酸化位点。我们发现，在DNA切口前后，凋亡细胞中H3 T45（H3 T45 ph）的磷酸化急剧增加。为了进一步探索这种联系，我们分析了人类中性粒细胞，因为它们是在体内经历凋亡的短寿命细胞。新鲜分离的中性粒细胞含有很少的H3 T45 ph，而培养20小时的细胞具有显着的量; H3 T45 ph诱导的动力学密切平行的caspase-3激活。中性粒细胞凋亡的细胞因子抑制导致H3 T45 ph水平降低。我们确定蛋白激酶C-δ作为负责H3 T45 ph在体外和体内的激酶。鉴于H3 T45的核小体位置，我们假设H3 T45 ph诱导核小体内的结构变化，以促进DNA切口和/或片段化。
Numerous post-translational modifications have been identified in histones. Most of these occur within the histone tails, but a few have been identified within the histone core sequences. Histone core post-translational modifications have the potential to directly modulate nucleosome structure and consequently DNA accessibility. Here, we identify threonine 45 of histone H3 (H3T45) as a site of phosphorylation in vivo. We find that phosphorylation of H3T45 (H3T45ph) increases dramatically in apoptotic cells, around the time of DNA nicking. To further explore this connection, we analyzed human neutrophil cells because they are short-lived cells that undergo apoptosis in vivo. Freshly isolated neutrophils contain very little H3T45ph, whereas cells cultured for 20 h possess significant amounts; the kinetics of H3T45ph induction closely parallel those of caspase-3 activation. Cytokine inhibition of neutrophil apoptosis leads to reduced levels of H3T45ph. We identify protein kinase C-delta as the kinase responsible for H3T45ph in vitro and in vivo. Given the nucleosomal position of H3T45, we postulate that H3T45ph induces structural change within the nucleosome to facilitate DNA nicking and/or fragmentation.