Chromosome inverted fusions, dicentrics and genome instability

染色体倒置融合、双着丝粒和基因组不稳定性

基本信息

批准号：
8373321
负责人：
TED A. WEINERT
金额：
$ 30.09万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2016-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Genome rearrangements are changes to cells chromosomes that can cause pathology. Genome rearrangements common in cells, and arise due to errors in cell duplication. One type, called a large scale rearrangement, is particularly deleterious to a cell; it can change the number of certain genes, can mutate a gene, and can generate unstable chromosomes that continue to rearrange. In humans it is clear that large scale rearrangements indeed cause significant pathology, a most famous case being the Philadelphia Chromosome where parts of Chr22 and Ch9 fuse, forming a gene fusion that causes leukemia. Recent deep sequencing of cancer genomes reveals a bewildering array of large scale changes; in some chromosomes appear to have exploded and pieced back together randomly, in others there are chains of chromosomes joined together. As mentioned, large scale rearrangements also form inherently unstable chromosomes, including dicentrics that contain two centromeres and are thus unstable. One particular rearrangement arises at a high frequency in pancreatic cancer cells. It's called a fold back inversion, where a chromosome fuses with itself such that it should form a dicentric. Why are fold back inversions of particular interest to us? We have developed a budding yeast chromosome instability system allows us to study large scale rearrangements. We have now identified a fold back inversion type chromosome change (that we call an inverted fusion), in yeast, that indeed forms dicentrics. Such fusions appear to occur frequently in the yeast genome, though we do not yet know where or how frequently. We have studied the mechanism of how this yeast inverted fusion/fold back inversion forms, and propose a model we can test. In this proposal, we will identify sequences in yeast that fuse to form dicentrics. This will provide information on how common fusions may be in the human genome. We will study how fusions occur, important for knowing how fusions occur in pancreatic cells and how they are avoided in normal human cells. Finally, we will establish genetic systems in fission yeast and in human cells to study fold back inversions. This will allow us to begin to directly understand how foldback inversion types of rearrangements arise in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Chromosome rearrangements and dicentrics cause human disease, and they form is not well understood. Using budding, fission and human cell systems, we will study how one prominent rearrangement, termed a inverted or fold back inversion, generates dicentric chromosomes. Fold back inversions are particularly of interest as they are common in pancreatic cancer.

描述（由申请人提供）：基因组重排是可能导致病理学的细胞染色体的变化。基因组重排在细胞中，并且由于细胞重复的错误而引起。一种称为大规模重排的类型对细胞特别有害。它可以改变某些基因的数量，可以突变基因，并可以产生继续重新排列的不稳定染色体。在人类中，很明显，大规模重排确实引起了重要的病理学，这是一个最著名的病例，是费城染色体，其中Chr22和Ch9 Fuse的一部分形成了引起白血病的基因融合。最近对癌症基因组的深度测序表明，大规模变化令人困惑。在某些染色体中，似乎已经随机爆炸并拼凑在一起，而在另一些染色体中，有染色体链条融合在一起。如前所述，大规模重排也形成了固有的不稳定染色体，包括包含两个centromeres且因此不稳定的双齿。一个特定的重排是在胰腺癌细胞中高频出现的。它称为折叠式倒置，其中染色体与自己融合，以使其应形成二分之一。为什么我们特别感兴趣的折叠反转？我们已经开发了一个发芽的酵母染色体不稳定性系统，使我们能够研究大规模的重排。现在，我们已经在酵母中确定了折叠式反转类型的染色体变化（我们称为倒融合）确实形成了dicentrics。这种融合似乎在酵母基因组中经常发生，尽管我们还不知道在哪里或频率。我们研究了这种酵母如何倒融合/折叠反转形式的机制，并提出了可以测试的模型。在此提案中，我们将确定在酵母中融合形成小齿的序列。这将提供有关人类基因组中常见融合的信息。我们将研究如何发生融合，对于了解胰腺细胞中的融合方式以及如何在正常人类细胞中避免它们。最后，我们将在裂变酵母和人类细胞中建立遗传系统，以研究折叠式反转。这将使我们能够开始直接了解胰腺癌的折叠反转类型。公共卫生相关性：染色体的重排和双齿引起人类疾病，它们形成并不理解。使用萌芽，裂变和人类细胞系统，我们将研究一个突出的重排如何被称为倒置或折叠反转的倒置染色体。折叠式反转特别感兴趣，因为它们在胰腺癌中很常见。