Mechanisms and functions of chromatin regulation for cell-cycle control

 描述（由申请方提供）：拟议研究的广泛、长期目标是在分子水平上确定调节染色质结构以进行适当细胞周期控制的机制。染色质调控在多种DNA依赖性过程中起着不可或缺的作用，包括转录、DNA复制、DNA修复、重组、动粒形成和DNA损伤检查点反应。因此，阐明染色质调控的机制是理解这些重要过程是如何控制的必要前提。研究染色质调控的主要挑战之一是阐明染色质调控如何在重要的生物学背景下影响如此广泛的过程，如细胞周期控制和细胞分化。这是一个特别重要的挑战，因为最近确定染色质调节因子中的突变代表了所谓的癌症驱动突变的一个主要类别，并且这些突变如何加速癌症发展仍然未知。因此，阐明染色质调控的机制不仅影响研究DNA依赖过程的基本原理的研究人员，而且也影响研究癌症生物学和基因组稳定性维持机制的研究人员。 我们的实验室一直有兴趣了解染色质调控如何有助于正确的细胞周期进程。我们最近开始研究细胞静止的分子机制。适当控制静止对于维持干细胞群体和预防癌症是必不可少的。然而，控制进入和维持静止细胞状态的分子机制在很大程度上是未知的。最近发现芽殖酵母S.酿酒酵母可以进入与哺乳动物的静止状态有许多共同特性的静止状态，并且开发了纯化静止细胞的方法。利用这一系统，我们发现，两个高度保守的染色质调节发挥核心作用，在进入静止。我们还发现，酵母细胞从静止状态释放后的第一个S期的DNA复制与有丝分裂细胞周期中的复制有很大不同，并且与哺乳动物DNA复制有重要的共同点。此外，我们有证据表明，适当的染色质调节在启动第一次DNA复制中起着特别重要的作用。最后，我们已经获得的证据表明，染色质调控起着关键作用，在有丝分裂细胞周期中的复制起点使用的时间确定。我们将利用这些最新的发现，并确定如何染色质调节有助于适当的细胞周期控制。

 DESCRIPTION (provided by applicant): The broad, long term goal of the proposed study is to determine, at the molecular level, mechanisms by which chromatin structure is regulated for proper cell cycle control. Chromatin regulation plays integral roles in a wide variety of DNA-dependent processes, including transcription, DNA replication, DNA repair, recombination, kinetochore formation, and DNA damage checkpoint response. Therefore, elucidating the mechanisms of chromatin regulation is a necessary prerequisite for understanding how these essential processes are controlled. One of the major challenges in studying chromatin regulation is to elucidate how chromatin regulation affects such a wide variety of processes in the context of important biological contexts, such as cell cycle control and cell differentiation. This is a particularly important challenge, because it was recently determined that mutations in chromatin regulators represent one major class of so called cancer driver mutations, and how these mutations accerelate cancer development remains unknown. Therefore, elucidating the mechanisms of chromatin regulation impacts not only the researchers who study fundamental principle of DNA-dependent processes, but also those who investigate cancer biology and mechanisms of genome stability maintenance. Our lab has been interested in understanding how chromatin regulation contributes to proper cell cycle progression. We have recently started investigating molecular mechanisms underlying cell quiescence. Proper control of quiescence is essential for the maintenance of stem cell population and prevention of cancer. However, molecular mechanisms that control the entry and maintenance of quiescent cell state have been largely unknown. It was recently found that the budding yeast S. cerevisiae can enter quiescent state that share many properties with mammalian quiescence, and a method to purify the quiescent cell was developed. Taking advantage of this system, we have found that two highly conserved chromatin regulators play central roles in the entry into quiescence. We have also found that DNA replication in the first S phase after yeast cells are released from quiescence is very different from replication in mitotic cell cycle, and shares an important aspect with mammalian DNA replication. Furthermore, we have evidence that proper chromatin regulation plays especially important roles in the initiation of the first DNA replication. Finally, we have obtained evidence that chromatin regulation plays a critical role in determining the timing of replication origin usage during the mitotic cell cycle. We will take advantage of these recent findings and determine how chromatin regulation contributes to proper cell cycle control.