Mechanisms and functions of chromatin regulation for cell-cycle control

细胞周期控制染色质调控的机制和功能

基本信息

批准号：
9062463
负责人：
TOSHIO TSUKIYAMA
金额：
$ 38.88万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9062463
关键词：
Accounting Address Affect Back Biological Biological Process Cancer Biology Cell Cycle Progression Cell Cycle Regulation Cell Differentiation process Cell Survival Cell division Cells Characteristics Chromatin Chromatin Structure DNA DNA Damage DNA Repair DNA biosynthesis DNA damage checkpoint DNA replication fork Development Division of Cancer Prevention Fire - disasters Genetic Recombination Genetic Transcription Genome Genome Stability Goals Health Histone Deacetylase Kinetochores Laboratories Maintenance Malignant Neoplasms Mammalian Cell Methods Mitotic Cell Cycle Modeling Molecular Mutation Normal Cell Nucleosomes Organism Play Positioning Attribute Process Property Regulation Replication Origin Repression Research Research Personnel Role S Phase Saccharomyces cerevisiae Saccharomycetales Site Switch Genes System Testing Time Transcriptional Regulation Yeasts actionable mutation cancer prevention in vivo interest stem cell population

项目摘要

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.

描述（由适用提供）：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。染色质调节在多种DNA依赖性过程中扮演着不可或缺的作用，包括转录，DNA复制，DNA修复，重组，动力学组形成和DNA损伤检查点响应。因此，阐明染色质调节的机制是了解如何控制这些基本过程的必要先决条件。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环境（例如细胞周期控制和细胞分化）的背景下影响如此广泛的过程。这是一个特别重要的挑战，因为最近确定染色质调节剂中的突变代表了所谓的癌症驱动突变的一个主要类别，以及这些突变如何加速癌症的发展仍然未知。因此，阐明染色质调节的机制不仅会影响研究DNA依赖性过程基本原理的研究人员，而且还影响了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。适当控制静止对于维持干细胞群体和预防癌症至关重要。但是，控制静脉细胞态进入和维持的分子机制在很大程度上是未知的。最近发现，发芽的酵母菌酿酒酵母可以输入静止状态，这些静态状态具有许多与哺乳动物静止的特性，并且是一种净化静脉细胞利用该系统的方法，我们发现两个高度保守的染色质调节剂在进入静脉曲张中起着核心作用。我们还发现，从静止中释放酵母细胞后的第一阶段的DNA复制与有丝分裂细胞周期中的复制大不相同，并且与哺乳动物DNA复制具有重要方面。此外，我们有证据表明，适当的染色质调节在开始第一个DNA复制中起着特别重要的作用。最后，我们获得了证据表明，染色质调节在确定有丝分裂细胞周期中复制起源的时间的时间内起关键作用。我们将利用这些最近的发现，并确定染色质调节如何促进适当的细胞周期控制。