INTERACTIONS OF THE MCM PROTEINS AT REPLICATION ORIGINS

MCM 蛋白在复制起点的相互作用

基本信息

批准号：
6519162
负责人：
BIK-KWOON TYE
金额：
$ 34.58万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-04-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6519162
关键词：
DNA footprinting DNA replication origin Saccharomyces cerevisiae cell cycle cell cycle proteins fungal genetics fungal proteins gene mutation protein protein interaction transcription factor

项目摘要

The initiation of DNA synthesis is a complex multi-step process that requires the coordinated actions of a number of replication initiation factors. This process begins with the ordered assembly of a pre- replication complex (pre-RC) at replication origins during the G1 phase. Studies in Saccharomyces cerevisiae indicate that the pre-RC consists of evolutionarily conserved replication initiation factors that include the origin recognition complex, ORC, a complex of sib subunits, and the Mcm2-7 proteins, a family of six homologous proteins. Initiation of DNA synthesis is activated by the successive phosphorylations of components of the pre-RC by at least two Cdks (cyclin dependent kinases) or Cdk- like kinases, Cdc28-Clb and Cdc-7-Dbf4. Initiation of DNA synthesis at replication origins is accompanied by a transition of the pre-RC to the elongation complex. As the elongation complex migrates away from the replication origin, the pre-RC is replaced by the post-replication complex (post-RC), which appears to include the ORC but not the other known components of the pre-RC. Previous studies showed that Mcm10 physically interacts with members of the Mcm2-7 proteins. We will investigate the multiple roles of Mcm10 in the assembly and disassembly of the pre-RC and its role in the migration of elongation forms in conjunction with the Mcm2-7 proteins. Significant efforts will also be devoted to the analysis of the functional relationship between Mcm10 and other components of the pre-RC. These studies should provide information about the mechanism that restricts DNA synthesis to once per cell cycle in eukaryotes. Cancer cells are characterized by their unregulated cell divisions. This study addresses a fundamental problem in the control of DNA replication and cell division using Saccharomyces cerevisiae as the model. Through understanding of normal cellular processes that regulate DNA replication, it may be possible to elucidate the molecular basis for abnormalities or defects that lead to the disease state in cancer cells.

DNA合成的启动是一个复杂的多步骤过程需要许多复制启动的协调动作因素。此过程始于预先组装在G1阶段复制起源处的复制复合物（PRE-RC）。酿酒酵母的研究表明，前RC由进化保守的复制引发因素包括 Origin识别复合物，兽人，一个SIB亚基的复合物， MCM2-7蛋白，一个六个同源蛋白的家族。 DNA的启动成分的连续磷酸化激活了合成至少两个CDK（细胞周期蛋白依赖性激酶）或CDK- 像激酶一样，CDC28-CLB和CDC-7-DBF4。 DNA合成的开始复制起源伴随着前RC的过渡伸长络合物。随着伸长综合体从复制起源，前RC被复制后取代复杂（post-rc），似乎包括兽人，但不包括另一个 PRE-RC的已知成分。先前的研究表明MCM10 与MCM2-7蛋白的成员物理相互作用。我们将研究MCM10在组装和拆卸中的多重作用前RC及其在伸长形式迁移中的作用与MCM2-7蛋白的结合。重大努力也将是致力于分析MCM10和前RC的其他组件。这些研究应提供信息关于将DNA合成限制为每个细胞周期一次的机制在真核生物中。癌细胞的特征是其不受管制的细胞部门。这项研究解决了控制的基本问题 DNA复制和细胞分裂使用酿酒酵母作为模型。通过了解调节的正常细胞过程 DNA复制，可能有可能阐明分子基础导致癌细胞中疾病状态的异常或缺陷。