Chromosome Inheritance

了解人类细胞中染色体的遗传机制是人类研究的一个基本问题 生物学，并与癌症研究有直接关系。对正常遗传模式的改变 肿瘤基因组中体细胞遗传异常的积聚促进肿瘤进展 细胞。本计划项目中其他人研究的调控途径直接控制DNA 复制和有丝分裂。拟议中的研究集中在细胞如何复制和分离染色体和 是基于观察到人类细胞中的起源识别复合体(ORC)参与了许多 这些过程。ORC是启动DNA复制所必需的，最近的研究表明 ORC或ORC亚基参与染色体遗传和细胞分裂的其他方面。这个 First Aim将解决ORC在细胞分裂周期中的动态组装问题，并确定如何 流程是受监管的。第二个目标是鉴定和鉴定染色体中的ORC相关蛋白。 遗传，使用蛋白质组学方法(核心D)和遗传方法以及RNAi文库(核心 B)发现爱泼斯坦-巴尔病毒复制所必需的细胞蛋白。第三个目标将扩大研究 ORC在异染色质维持中的作用及其与RNAi机制的潜在关系 维持异染色质。最终目的将研究ORC亚单位在中心体复制和 控制染色体分离。尽管细胞分裂周期调节机制协调 染色体遗传周期的多个阶段，该项目的研究提出了一个更基本的 DNA复制的实际过程和染色体分离之间的联系。因此，这些 对染色体遗传的研究直接关系到该项目的总体目标和 本计划中的其他项目。

Understanding the mechanism of inheritance of chromosomes in human cells is a fundamental problem in biology and has direct relevance to cancer research. Alterations to the normal pattern of inheritance promote progression to cancer by the accumulation of somatic genetic aberrations in the genome of tumor cells. The regulatory pathways investigated by others in this Program Project directly control the DNA replication and mitosis. The proposed studies focus how a cell duplicates and segregates chromosomes and are based on the observation that Origin Recognition Complex (ORC) in human cells participates in many of these processes. ORC is required for the initiation of DNA replication and recent research has demonstrated that ORC, or ORC subunits participate in other aspects of chromosome inheritance and cell division. The first aim will address the dynamic assembly of ORC during the cell division cycle and determine how this process is regulated. A second aim will identify and characterize ORC associated proteins in chromosome inheritance, suing both proteomic methods (with Core D) and genetic approaches with an RNAi library (Core B) to discover cellular proteins essential for Epstein Barr Virus replication. A third aim will expand research on the role of ORC in maintenance of heterochromatin and a potential relationship with the RNAi machinery maintaining heterochromatin. A final aim will study the role of ORC subunits in centrosomes duplication and control chromosome segregation. Although the cell division cycle regulatory machinery coordinates the multiple stages of the chromosome inheritance cycle, research in this Project suggests a more fundamental connection between the actual processes of DNA replication and chromosome segregation. Thus these studies on chromosome inheritance are directly relevant to the overall goals of the program project and the other projects in the Program.