Function of CAF-1 in Epigenetic Inheritance

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 保持基因组的完整性。一旦形成，异染色质必须在细胞分裂过程中传递到子细胞。 细胞分裂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，我们认为， 关于异染色质如何在S期遗传或表观遗传的研究不仅会增加 我们对这一基本生物过程的理解，也揭示了这一过程是如何出错的， 癌细胞 酵母S. cerevisiae提供了一个很好的模型系统来研究表观遗传。酵母 异染色质的特点是存在低乙酰化的历史和四个沉默的信息调节 (Sir)proteins. SirSp和Sir 4p与低乙酰化组蛋白H3和H4相关， 酵母沉默染色质的维持。在DNA合成过程中，许多表观遗传信息， 对组蛋白和Sir蛋白的修饰被暂时中断。DNA合成后， 表观遗传信息必须重建。染色质组装因子1（Chromatin assemblyfactor 1，CAF-1）是其中一个因子 参与表观遗传信息的遗传。然而，CAF-1的分子机制 在这个过程中的作用并不明确。 我们的长期目标是了解细胞S期期间染色质结构是如何遗传的 周期本研究的目的是研究CAF-1发挥作用的分子机制， 调节和效应蛋白继承沉默染色质结构在酵母。这些研究将探讨如何 异染色质在酵母中是遗传的。此外，从这些研究中获得的知识也将导致 更好地理解表观遗传在乳腺癌细胞和癌症所造成的故障， 过程

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 processgoes awry in cancer cells. The yeast S. cerevisiae offers an excellent model systemto 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 H4for 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 DNAsynthesis, the epigenetic information must be reestablished. Chromatin assemblyfactor 1 (CAF-1) is one of the factors involved in inheritance of epigenetic information. However, the molecular mechanisms by whichCAF-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-1functions wtih its modulator and effectorproteins 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 understaning of epigenetic inheritance in mammaliancells and cancer caused by malfunction of this process.