Mechanisms and functions of chromatin regulation for cell-cycle control

 描述(由申请人提供)：拟议研究的广泛的、长期的目标是在分子水平上确定染色质结构被调节以进行适当的细胞周期控制的机制。染色质调节在广泛的DNA依赖过程中发挥着不可或缺的作用，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，阐明染色质调节的机制是了解这些重要过程是如何被控制的必要前提。研究染色质调节的主要挑战之一是阐明染色质调节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，因为最近人们确定，染色质调节器的突变代表了一种主要的所谓癌症驱动突变，而这些突变如何加速癌症的发展仍不清楚。因此，阐明染色质调控的机制不仅关系到研究DNA依赖过程的基本原理，也关系到癌症生物学和基因组稳定性维持机制的研究。我们的实验室一直有兴趣了解染色质调节如何有助于适当的细胞周期进程。我们最近开始研究细胞静止的分子机制。适当地控制静止状态对于维持干细胞数量和预防癌症至关重要。然而，控制细胞静止状态进入和维持的分子机制在很大程度上还不清楚。最近发现，芽生酵母可以进入静止状态，这与哺乳动物的静止状态具有许多共同的性质，并开发了一种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因子在进入静止状态的过程中发挥着核心作用。我们还发现，酵母细胞从静止状态解脱后的第一个S时相的复制与有丝分裂细胞周期中的复制有很大的不同，并与哺乳动物的复制有一个重要的方面。此外，我们有证据表明，适当的染色质调节在第一次DNA复制的启动中发挥着特别重要的作用。最后，我们得到的证据表明，在有丝分裂细胞周期中，染色质调节在决定复制起始点的使用时间方面起着关键作用。我们将利用这些最新的发现，并确定染色质调节如何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.