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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8373321
• 关键词: Back; Cell Cycle; Cells; Centromere; Chromosomal Instability; Chromosomes; Complex; DNA; DNA Sequence; DNA Sequence Rearrangement; DNA biosynthesis; Dicentric chromosome; Disease; Event; Failure; Fission Yeast; Frequencies; Fungal Genome; Gene Dosage; Gene Fusion; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Grant; Human; Human Chromosomes; Human Genome; Human Pathology; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammals; Methods; Modeling; Molecular; Mutate; Nature; Oncogene Activation; Pancreas; Pathology; Pathway interactions; Philadelphia Chromosome; Positioning Attribute; Proteins; Replication Error; Role; S Phase; Saccharomycetales; Site; Stress; Structure; System; Testing; Yeasts; base; cancer genome; genome-wide; human disease; interest; leukemia; novel; pancreatic cancer cells; prevent; research study; tool

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）：基因组重排是细胞染色体的变化，可能导致病理。基因组重排在细胞中很常见，并且是由于细胞复制错误而引起的。其中一种称为大规模重排，对细胞特别有害。它可以改变某些基因的数量，可以使基因突变，并可以产生持续重新排列的不稳定染色体。在人类中，很明显大规模的重排确实会引起显着的病理学，最著名的例子是费城染色体，其中部分 Chr22 和 Ch9 融合，形成导致白血病的基因融合。最近的癌症基因组深度测序揭示了一系列令人眼花缭乱的大规模变化；在一些染色体中，似乎已经爆炸并随机拼凑在一起，而在另一些染色体中，则有染色体链连接在一起。如前所述，大规模重排也会形成本质上不稳定的染色体，包括含有两个着丝粒的双着丝粒，因此不稳定。胰腺癌细胞中频繁出现一种特殊的重排。这称为折返倒位，即染色体与自身融合，从而形成双着丝粒。为什么我们对折返反转特别感兴趣？我们开发了出芽酵母染色体不稳定系统，使我们能够研究大规模重排。我们现在已经在酵母中发现了折返倒置型染色体变化（我们称之为倒置融合），它确实形成了双着丝粒。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发生频率如何。我们研究了这种酵母倒置融合/折回倒置如何形成的机制，并提出了一个可以测试的模型。在本提案中，我们将鉴定酵母中融合形成双着丝粒的序列。这将提供有关人类基因组中融合的常见程度的信息。我们将研究融合如何发生，这对于了解胰腺细胞如何发生融合以及如何在正常人类细胞中避免融合非常重要。最后，我们将在裂殖酵母和人类细胞中建立遗传系统来研究折返反转。这将使我们能够开始直接了解胰腺癌中折返反转类型的重排是如何出现的。 公共卫生相关性：染色体重排和双着丝粒会导致人类疾病，但人们对它们的形成尚不清楚。利用出芽、裂变和人类细胞系统，我们将研究一种显着的重排（称为倒置或折回倒置）如何产生双着丝粒染色体。折返倒置特别令人感兴趣，因为它们在胰腺癌中很常见。