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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：
10616221
负责人：
TOSHIO TSUKIYAMA
金额：
$ 3.89万
依托单位：
FRED HUTCHINSON CANCER 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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10616221
关键词：
Mechanisms functions chromatin regulation cell

项目摘要

Project Summary/Abstract which cell-cycle is regulated, with an emphasis on mechanisms of cell quiescence through chromatin regulation. Eukaryotic cells, from single cell organisms to humans, spend most of their time in quiescence, in which cell exit mitotic cell-cycle in a reversible fashion for long-term survival. Proper control of entry into, maintenance of, and exit from quiescence is essential for cell survival, normal development of organisms, stem cell maintenance and prevention of cancer. However, molecular mechanisms underlying quiescence remains largely unknown. 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. 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 strong evidence that degradation of specific sets of mRNA is essential for quiescence entry. This strongly suggest the presence of currently unknown mechanism to regulate quiescence entry. We have also found that the high-order structure of chromatin is regulated in quiescence in a way distinct from exponentially growing cells. First, we found that condensin, a highly conserved regulator of chromatin higher-order structure, globally re-localizes during quiescence entry and play key roles in chromatin domain structure in quiescent cells. Secondly, we found that nucleosome arrays are folded into different fashion in quiescent cells. We will take advantage of these recent findings and determine the molecular basis for these observations, which will address a significant gap in our current knowledge about mechanisms underlying quiescence and higher-order chromatin structure.

项目摘要/摘要哪个细胞周期受调节，重点是通过染色质调节细胞静止的机制监管。真核细胞，从单细胞生物到人类，它们的大部分时间都花在静止期，细胞以可逆的方式退出有丝分裂细胞周期，以获得长期生存。恰如其分控制进入、维持和退出静止状态是细胞正常生存所必需的生物体的发展、干细胞的维持和癌症的预防。然而，分子静默背后的机制在很大程度上仍不清楚。染色质调节起着不可或缺的作用在广泛的DNA依赖过程中，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，澄清染色质调节的机制是理解这些基本过程是受控的。研究染色质调节的主要挑战之一是阐明染色质调节是如何影响如此广泛的过程的生物学背景，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器的突变代表一种主要类别的所谓癌症驱动突变，以及这些突变如何加速癌症发展情况仍不得而知。因此，阐明染色质调节影响的机制不仅是研究DNA依赖过程基本原理的研究人员，还有那些他们研究癌症生物学和基因组稳定性维持的机制。最近发现，发芽酵母可以进入静止状态，分享哺乳动物具有静止细胞的许多性质，并发展了一种纯化静止细胞的方法。利用这一系统，我们发现了强有力的证据表明，特定集合的退化 M RNA是静息进入所必需的。这强烈地表明了目前未知的调节静止进入的机制。我们还发现染色质的高阶结构以一种不同于指数增长的细胞的方式在静止状态下进行调节。首先，我们发现，凝集素是染色质高阶结构的高度保守的调节因子，在静止期进入并在静止期细胞染色质结构域结构中起关键作用。其次，我们发现在静止的细胞中，核小体阵列以不同的方式折叠。我们会带上利用这些最新的发现，并确定这些观察的分子基础，这将解决我们目前对静止和静止背后的机制的认识中的一个重大差距高阶染色质结构。