Function of CAF-1 in Epigenetic Inheritance

描述（由申请人提供）：在真核细胞中，异染色质控制多种细胞过程，如沉默转录和维持基因组完整性。一旦形成，异染色质必须在细胞分裂期间传递到子细胞。异染色质结构的不适当获得或丧失在癌症中起着因果作用。因此，关于异染色质在S期或表观遗传期间如何遗传的研究不仅将增加我们对这一基本生物学过程的理解，而且还将阐明这一过程在癌细胞中是如何出错的。 酵母S.酿酒酵母为研究表观遗传提供了极好的模型系统。酵母异染色质的特点是存在hypoacetylated的历史和四个沉默的信息调节（先生）蛋白。SirSp和Sir 4p与低乙酰化组蛋白H3和H4结合，用于建立和维持酵母沉默染色质。在DNA合成过程中，许多表观遗传信息，如组蛋白和Sir蛋白的修饰，都被暂时破坏。DNA合成后，表观遗传信息必须立即重建。染色质组装因子1（CAF-1）是参与表观遗传信息遗传的因子之一。然而，CAF-1在这一过程中发挥作用的分子机制尚不清楚。 我们的长期目标是了解染色质结构在细胞周期的S期是如何遗传的。本研究的目的是研究CAF-1与其调节蛋白和效应蛋白在酵母中遗传沉默染色质结构的分子机制。这些研究将阐明异染色质在酵母中是如何遗传的。此外，从这些研究中获得的知识也将导致更好地理解哺乳动物细胞中的表观遗传遗传和由这一过程故障引起的癌症。

DESCRIPTION (provided by applicant): In eukaryotic cells, heterochromatin governs diverse cellular processes such as silencing transcription and maintaining genomic integrity. Once formed, heterochromatin must be transmitted to daughter cells during cell division. Inappropriate gain or loss of heterochromatic structure plays a causal role in cancer. Therefore, studies on how heterochromatin is inherited during S phase or epigenetic inheritance will not only increase our understanding of this basic biological process, but also shed light on how this process goes awry in cancer cells. The yeast S. cerevisiae offers an excellent model system to study epigenetic inheritance. Yeast heterochromatin is marked by the presence of hypoacetylated histories and four silent information regulator (Sir) proteins. SirSp and Sir4p associate with hypoacetylated histones H3 and H4 for establishment and maintenance of yeast silent chromatin. During DNA synthesis, much of the epigenetic information such as modifications on histones as well as Sir proteins is temporarily disrupted. Immediately after DNA synthesis, the epigenetic information must be reestablished. Chromatin assembly factor 1 (CAF-1) is one of the factors involved in inheritance of epigenetic information. However, the molecular mechanisms by which CAF-1 functions in this process is not clear. Our long-term goal is to understand how chromatin structures are inherited during the S phase of the cell cycle. The objective of this proposal is to study molecular mechanisms whereby CAF-1 functions with its modulator and effector proteins to inherit silent chromatin structure in yeast. These studies will address how heterochromatin is inherited in yeast. Moreover, knowledge gained from these studies will also lead to a better understanding of epigenetic inheritance in mammalian cells and cancer caused by malfunction of this process.