Swc5特异识别H2A并促进H2A.Z交换的结构和分子机制研究

The structure of chromatin was regulated by kinds of chromatin remodelers, which is very important for maintaining the genomic stability and integrity. SWR1 complex, one of the most important chromatin remodeler, promotes the replacement of H2A/H2B with H2A.Z/H2B in an ATP-consuming manner at specific gene sites where H2A.Z functions as a regulator. The previous researches showed that the ATPase activity of SWR1 complex was stimulated by its substrates, the nucleosomes containing H2A/H2B and free H2A.Z/H2B dimers. Besides the substrates, the latest research has shown that H2A/H2B, the production of the enzymatic reaction, also influences the efficiency of the exchange process. Importantly, Swc5, a subunit of SWR1 complex, plays a critical role in assisting H2A ejection during the exchange process. Applicant has focused on the mechanism of SWR1 complex in regulating the structure of chromatin, and elucidated the principle of recognition of H2A.Z/H2B by SWR1 complex subunit YL1 in the past years. Here, by applying a combination of structural, biochemical and genetic approaches, we would address the functional roles of Swc5 in regulating the efficiency of enzymatic reaction of SWR1 complex by specific recognition of H2A and Swr1. The knowledge we gain in this study is critical to fully understand not only the mechanism of H2A.Z positioned to genome by SWR1 complex, but also the intricate rules which govern epigenetic regulation.

染色质重塑复合物通过调节染色质结构进而影响生命活动的正常完成。染色质重塑复合物SWR1通过水解ATP促进组蛋白变体H2A.Z/H2B替换核小体中的H2A/H2B，从而使H2A.Z定位在特定位点发挥其生物学功能。早先的研究发现SWR1复合物的酶促活性受到底物核小体，游离的H2A.Z/H2B二聚体的调控。最新的研究证实除了底物之外，其酶促反应产物H2A/H2B二聚体同样影响反应效率，而这一过程很可能受到SWR1的亚基Swc5的调控。申请人的前期工作集中在SWR1复合物的工作原理方面，并部分阐释了SWR1复合物与底物H2A.Z/H2B相互作用的机制。在本项目中，申请人拟采用结构生物学、生物化学、酵母遗传学等多种方法揭示Swc5亚基特异性识别H2A以及Swr1进而调控SWR1复合物酶促反应的作用机制。本项目对于阐明SWR1复合物调控H2A.Z在基因组的定位机制具有重要意义。

染色质重塑复合物通过调节染色质结构进而影响生命活动的正常完成。染色质重塑复合物SWR1通过水解ATP促进组蛋白变体H2A.Z/H2B替换核小体中的H2A/H2B，从而使H2A.Z定位在特定位点发挥其生物学功能。研究发现SWR1复合物的酶促活性受到底物核小体，游离的H2A.Z/H2B二聚体的调控。最新的研究证实除了底物之外，其酶促反应产物H2A/H2B二聚体同样影响反应效率，而这一过程很可能受到SWR1的亚基Swc5的调控。因此研究swc5与H2A的相互关系对理解swr1复合物的作用机制具有重要意义。本课题拟采用结构生物学、生物化学、酵母遗传学等多种方法揭示Swc5亚基特异性识别H2A以及Swr1进而调控SWR1复合物酶促反应的作用机制。

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