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首页> 外文会议>American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics >Dynamic Phosphorylation Regulates Histone Deacetylase Localization, Interactions, and Cell Cycle-dependent Functions
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Dynamic Phosphorylation Regulates Histone Deacetylase Localization, Interactions, and Cell Cycle-dependent Functions

机译：动态磷酸化调节组蛋白脱乙酰酶定位，相互作用和细胞周期依赖性功能

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Histone deacetylases (HDACs) are important transcriptional regulators whose activities are finely controlled by phosphorylation. HDAC mis-regulation is implicated in the progression of multiple human disease states, including viral infection (2), cancer (3), and cardiac disease (4). Reflecting their critical roles, HDAC inhibitors are currently used in anti-cancer treatments. HDACs exert their enzymatic functions as components of multi-protein complexes to mediate transcriptional repression (5-7). Site-specific phosphorylation and subsequent binding of 14-3-3 chaperone proteins promotes nuclear export of class IIa HDACs, thus relieving their function as repressors of transcription within the nucleus (8-10). HDACs and histone acetylatransferases are thought to be carefully regulated during cell cycle progression to maintain the acetylation states of histone targets, but the involved mechanisms remain to be elucidated. Mitotic progression is disrupted upon HDAC inhibition (11, 12), resulting in G2-phase checkpoint response (13, 14), chromosome instability (15), and defects in kinetochore assembly and attachment (16). However, the roles of class IIa HDACs during mitosis and their phosphorylation status throughout cell cycle progression have not previously been investigated. Moreover, a global understanding of phosphorylation-dependent protein interactions and their impact on downstream functions is still lacking. Here we report a comprehensive investigation of phosphorylation-dependent class IIa HDAC interactions and regulatory mechanisms. We demonstrate that specific phosphorylation sites do not only control HDAC localization, but also regulate cell-cycle dependent activity, interactions, and temporal transcriptional repression. We present evidence that phosphorylations within functional domains of class IIa HDACs are important for mediating protein interactions, and demonstrate for the first time that class IIa HDACs are regulated in a cell cycle-dependent manner via phosphorylation.
机译：组蛋白脱乙酰酶（HDACs）是重要的转录调节，其活动通过磷酸化被精细控制的。 HDAC误调节在多种人类疾病状态，包括病毒感染（2），癌症（3），和心脏疾病（4）的进展有关。反映了他们在关键的作用，HDAC抑制剂的抗癌治疗目前使用。 HDAC的发挥其酶功能的多蛋白复合物的成分介导的转录抑制（5-7）。现场具体磷酸化和随后14-3-3伴侣蛋白结合促进IIa类HDAC的核出口，从而减轻其功能为核心（8-10）内转录的阻遏。的HDACs和组蛋白acetylatransferases被认为是细胞周期进程中仔细地管理以维持组蛋白目标乙酰化状态，但发生机制有待阐明。有丝分裂进程中在HDAC抑制（11，12）破坏，从而产生G2期检查点响应（13，14），染色体的不稳定性（15），并且在着丝粒和装配附件（16）的缺陷。然而，IIa类HDAC的有丝分裂过程中的角色和整个细胞周期进程的磷酸化状态以前没有被查处。此外，依赖磷酸化的蛋白相互作用有全面的认识及其对下游的影响作用仍然缺乏。在这里，我们报告的磷酸化依赖的IIa类HDAC的相互作用和监管机制的全面调查。我们表明，特定的磷酸化位点不仅控制HDAC定位，还能调节细胞周期依赖性活动，互动和时间转录抑制。我们本证据表明，IIa类HDAC的功能性结构域磷酸化内是用于介导蛋白相互作用重要的，并且对于第一次IIa类HDAC是在细胞周期依赖性的方式通过磷酸化调节演示。

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