Chromosome Transmission Fidelity

染色体传输保真度

• 批准号: 6400729
• 负责人: FORREST A. SPENCER
• 金额: $ 30.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400729
• 关键词: DNA replication; Saccharomyces cerevisiae; cell cycle; chromosome movement; cytogenetics; fungal genetics; gene targeting; genetic crossing over; methylation; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): The set of processes ensuring high fidelity replication and segregation of genomes is comprised of both structural and regulatory steps. One fundamental aspect of chromosome segregation is the requirement for association of Sister chromatids, such that each member will be oriented towards a different spindle pole in metaphase alignment. Although many proteins required for sister chromatid cohesion have been identified in the past several years, little is known about how the highly specific and very tight chromatin associations are formed. We have recently found that two DNA replication-associated proteins are required for robust sister chromatid cohesion in budding yeast, substantially augmenting the evidence for establishment of cohesion during DNA synthesis. Here we propose to pursue the contributions of one of them (S. cerevisiae CTF18p) in detail, with the goal of understanding functional relationships between proteins that act in concert with the replication fork and proteins that form the physical bridges that hold sisters together until anaphase. Our approaches include investigation of both physiological and molecular functions of Ctfl8p, using standard molecular genetic techniques. We also propose development of a novel method for visualizing alterations of mitotic chromosome structure in budding yeast. This new method has the potential for substantially refining our view of mitotic chromosome structure, as well as differentiating among abnormalities exhibited by different mutants. The proteins that mediate structural and regulatory steps governing chromosome behavior in cell division are highly conserved throughout eukaryote biological systems. The aneuploidy arising from failures in chromosome transmission has significant consequences for human health, especially in the development of somatic disorders such as cancer and polycystic kidney disease, as well as constitutional aneuploidies in which a zygote is established from gametes of abnormal chromosome number. The relationship between DNA replication and sister chromatid cohesion is a newly appreciated aspect of the chromosome cycle, and it is anticipated that studies in the yeast model system will set the stage for the development of hypotheses to be tested in human cells, and avenues for understanding when or if dysfunction of this protein contributes to human aneuploidy.

描述（由申请人提供）：一套确保高 基因组的保真度复制和分离是由两个结构 和监管步骤。染色体分离的一个基本方面是 姐妹染色单体联合的要求，这样每个成员将是 在中期排列中朝向不同的纺锤体极。尽管许多 姐妹染色单体凝聚所需的蛋白质已经在 在过去的几年里，很少有人知道如何高度具体和非常 形成紧密的染色质结合。我们最近发现两个DNA 复制相关蛋白是强大的姐妹染色单体所必需的 凝聚力芽殖酵母，大大增加了证据， 在DNA合成过程中建立凝聚力。在这里，我们建议继续 其中之一的贡献（S。cerevisiae CTF18p）的详细信息，目标是 了解蛋白质之间的功能关系， 与复制叉和蛋白质形成的物理桥梁， 姐妹篇们在一起直到后期。我们的方法包括调查两者 Ctfl8p的生理和分子功能，使用标准分子生物学方法， 基因技术我们还提出了一种新的方法， 可视化芽殖酵母有丝分裂染色体结构的改变。这 一种新的方法有可能大大改善我们对有丝分裂的看法。 染色体结构，以及区分异常表现 不同的突变体。 调节染色体结构和调控步骤的蛋白质 细胞分裂行为在整个真核生物学中是高度保守的。 系统.染色体传递失败引起的非整倍体， 对人类健康的重大影响，特别是在发展 躯体疾病如癌症和多囊肾病，以及 组成性非整倍性，其中受精卵是由 染色体数目异常DNA复制与姐妹的关系 染色单体凝聚是染色体周期的一个新认识的方面， 预计酵母模型系统的研究将为 在人类细胞中进行测试的假设的发展，以及 了解这种蛋白质的功能障碍何时或是否有助于人类 非整倍性