Mechanisms and functions of ATP-dependent chromatin remodeling

ATP依赖性染色质重塑的机制和功能

• 批准号: 7847416
• 负责人: TOSHIO TSUKIYAMA
• 金额: $ 49.44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847416
• 关键词: Address; Affect; Biochemical; Biological; Biological Models; Biological Process; Cell Nucleus; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; DNA; DNA Repair; DNA biosynthesis; DNA replication fork; DNA-Directed DNA Polymerase; Functional RNA; Genes; Genetic Recombination; Genetic Transcription; Genome; Goals; Human Genome; ISWI; Intercistronic Region; Knowledge; Link; Malignant Neoplasms; Mediating; Meiosis; Modeling; Molecular; Molecular Genetics; Mutation; Nuclear; Nucleosomes; Pathway interactions; Phase; Play; Positioning Attribute; Process; Regulation; Replication Origin; Research; Retrotransposon; Role; Saccharomyces cerevisiae; Saccharomycetales; Slide; Stress; Testing; Transcript; Transfer RNA; Work; Yeasts; base; cell type; chromatin remodeling; gene repression; genome-wide; human disease; multidisciplinary

DESCRIPTION (provided by applicant): The broad, long-term goals of the proposed studies are to determine how chromatin structure affects nuclear processes, and how chromatin structure is regulated to accommodate these processes. These are fundamental questions because chromatin regulation affects virtually every biological process that take place in nucleus, including transcription, recombination, DNA repair and DNA replication. Consistent with their importance in understanding chromatin regulation, mutations in numerous chromatin regulators have been linked to human diseases, including cancer. Therefore, studying chromatin regulation will contribute not only to further identification of mechanisms governing basic biological processes, but also to understanding the molecular basis for human diseases. In our previous work, we found that a chromatin regulator Isw2 plays critical roles in both suppression of non-coding transcription and facilitation of DNA replication in our model system, budding yeast Saccharomyces cerevisiae. To elucidate mechanisms and functions of this intriguing chromatin regulator further, we will take multidisciplinary, complementary approaches. We will test our hypothesis that a major role of Isw2 is to be targeted to the ends of genes via a previously unidentified mechanism to protect the genome from abnormal non-coding transcription. In a parallel effort, we will investigate how this complex facilitates DNA replication using molecular genetic approaches. It has become clear that mutations in the human genome that cause abnormal chromatin regulation cause numerous human diseases, including cancer. Our proposed studies elucidate how major regulators of chromatin structure function in cells, contributing to a better understanding of the molecular basis for human diseases.

描述（由申请人提供）：拟议的研究的广泛长期目标是确定染色质结构如何影响核过程，以及如何调节染色质结构以适应这些过程。这些是基本问题，因为染色质调节实际上会影响核中发生的每个生物学过程，包括转录，重组，DNA修复和DNA复制。与它们在理解染色质调节中的重要性一致，许多染色质调节剂中的突变与包括癌症在内的人类疾病有关。因此，研究染色质调节不仅将有助于进一步鉴定有关基本生物学过程的机制，而且还将有助于理解人类疾病的分子基础。在我们先前的工作中，我们发现染色质调节剂ISW2在抑制非编码转录和促进DNA复制的促进酵母酵母糖酵母中的DNA复制方面起着至关重要的作用。为了进一步阐明这种有趣的染色质调节剂的机制和功能，我们将采用多学科的互补方法。我们将测试我们的假设，即ISW2的主要作用是通过先前未鉴定的机制靶向基因的末端，以保护基因组免受异常非编码转录的侵害。在平行的努力中，我们将研究这种复合物如何使用分子遗传方法促进DNA复制。很明显，引起异常染色质调节的人类基因组中的突变会导致许多人类疾病，包括癌症。我们提出的研究阐明了染色质结构在细胞中的主要调节剂如何有助于更好地理解人类疾病的分子基础。