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Cis-and trans-acting determinants of replication timing

复制时间的顺式和反式作用决定因素

基本信息

批准号：
7057820
负责人：
JOEL A HUBERMAN
金额：
$ 38.22万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2008-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): One of the cellular alterations required for development of cancer is "genomic instability," a term that describes a collection of pathways all leading to increased frequency of gene mutation and altered patterns of gene expression. Among the mechanisms causing genomic instability are chromosome breakage, gene amplification, and changes in levels of gene expression. The latter are frequently associated with changes in gene methylation status. All of these mechanisms have been correlated with changes in replication timing, and it is possible that in some cases changes in replication timing may be the primary cause of these phenomena. So far it has been difficult to evaluate the role of changes in replication timing in cancer development, because so little is known about the mechanisms controlling replication timing. Fortunately previous studies in budding and fission yeasts (Saccharomyces cerevisiae and Schizosaccharomyces pombe), in our laboratory and others, provide entry points into understanding replication timing. In both yeasts we have identified replication origins containing internal cis-acting sequences that determine late replication timing. Here we propose simple strategies that will permit us to precisely localize those sequences and use them to pull out the corresponding trans-acting proteins. In addition, studies in other laboratories and ours have already identified several proteins likely to play roles in replication timing. We intend to investigate the potential roles of all of these proteins in replication timing by studying the effects on timing of mutations in the corresponding genes and by studying the binary interactions between these proteins. The results of the proposed experiments should permit us to develop detailed models of the mechanisms controlling replication timing in both budding and fission yeasts. The conserved aspects of these models are likely to prove applicable to other eukaryotic cells, including human cells. This information may permit the development of drugs that will enhance normal replication timing stability and thus inhibit or reverse the development of cancer.

描述（由申请人提供）：癌症发展所需的细胞改变之一是“基因组改变”。不稳定性”这个术语描述了一系列的途径，基因突变频率增加，基因表达模式改变。引起基因组不稳定性的机制包括染色体断裂、基因突变、基因突变和基因突变。扩增和基因表达水平的变化。后者通常与基因甲基化状态的变化有关。所有这些机制与复制时间的变化相关，在某些情况下，复制时间的变化可能是主要的这些现象的原因。到目前为止，很难评估癌症发展中复制时间的变化，因为很少有了解控制复制定时的机制。幸运的先前在芽殖和裂殖酵母（酿酒酵母（Saccharomyces cerevisiae）和裂殖酵母），在我们的实验室和其他人，提供了切入点理解复制的时间在这两种酵母中，复制起点含有内部顺式作用序列，延迟复制计时。这里我们提出一些简单的策略，来精确定位这些序列，相应的反式作用蛋白。此外，其他研究我们的实验室和我们的实验室已经鉴定出几种蛋白质，复制时机中的角色。我们打算研究以下因素的潜在作用：所有这些蛋白质在复制时间上的作用，在相应的基因突变，并通过研究二进制这些蛋白质之间的相互作用。拟议实验的结果应该允许我们开发控制机制的详细模型，芽殖酵母和裂殖酵母的复制时间。保守的方面这些模型可能证明适用于其他真核细胞，包括人类细胞。这些信息可能有助于开发药物这将增强正常的复制定时稳定性，从而抑制或逆转癌症的发展。