Function of CAF-1 in Epigenetic Inheritance

描述(申请人提供)：在真核细胞中，异染色质控制着不同的细胞过程，如沉默转录和维持基因组完整性。异染色质一旦形成，就必须在细胞分裂过程中传递给子细胞。不适当的异染色质结构的获得或丢失在癌症中起着因果作用。因此，研究异染色质在S期或表观遗传过程中是如何遗传的，不仅将增加我们对这一基本生物学过程的理解，也将有助于揭示这一过程在癌细胞中是如何出错的。 酿酒酵母为研究表观遗传提供了一个很好的模型系统。酵母异染色质的特征是存在低乙酰化的历史和四个沉默的信息调节蛋白(SIR)。SirSp和Sir4p与低乙酰化组蛋白H3和H4结合，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，都会暂时中断。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是如何在细胞周期的S阶段遗传的。这项建议的目的是研究CAF-1与其调节器和效应蛋白一起在酵母中继承沉默染色质结构的分子机制。这些研究将解决酵母中异染色质是如何遗传的。此外，从这些研究中获得的知识也将有助于更好地理解哺乳动物细胞的表观遗传和这一过程故障导致的癌症。

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.