Suppression of duplication-mediated genome rearrangements by protein sumoylation

通过蛋白质苏酰化抑制重复介导的基因组重排

基本信息

批准号：
9148237
负责人：
HUILIN ZHOU
金额：
$ 31.18万
依托单位：
LUDWIG INSTITUTE FOR CANCER RES LTD
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9148237
关键词：
Address Alleles Biochemical Biochemistry Biological Models Cancer Diagnostics Cell Survival Chromosomal Rearrangement Chromosome Segregation Collection Copy Number Polymorphism DNA Repair DNA biosynthesis Development Elements Enzymes Essential Genes Eukaryota Eukaryotic Cell Exhibits Genes Genetic Genetic Transcription Genome Goals Hallmark Cell Health Human Human Genetics Human Genome Knowledge Lead Maintenance Malignant Neoplasms Maps Mediating Methods Mutation Nuclear Pathway interactions Post-Translational Protein Processing Process Property Protein Family Proteins Proteome Proteomics Regulation Repetitive Sequence Risk Role Saccharomyces cerevisiae Site Substrate Specificity Sumoylation Pathway Temperature Testing Yeasts base cancer genetics cell growth enzyme substrate forward genetics genetic analysis genome integrity helicase homologous recombination human disease improved insight isopeptidase mutant novel prevent protein function tool ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant) The human genome contains many "at-risk" sequences that are prone to mutations including diverse repeated sequences, segmental duplications and regions of copy number variations. Such repetitive sequence elements can cause genome rearrangements through non-allelic homologous recombination (HR). Many human diseases are known to be caused by chromosomal rearrangements mediated by non-allelic HR. Moreover, many cancers exhibit ongoing genome rearrangements, stimulated by numerous "at-risk" sequences in the genome. The yeast Saccharomyces cerevisiae provides a powerful model system to study genome rearrangements. Despite that many pathways have been found to suppress genome rearrangements, the understanding of how duplication-mediated genome rearrangements are specifically suppressed remains rudimentary. Sumoylation is an evolutionarily conserved post-translational modification of proteins and it is known to regulate many nuclear activities includin gene transcription, chromosome segregation, DNA replication and repair. We have discovered a new function of protein sumoylation in suppression of duplication- mediated genome rearrangement and found that the SUMO pathway is by far the most important pathway in preventing this type of genome rearrangements. In the proposed studies, we will characterize the genetics and biochemistry of the SUMO pathway focusing on its function in genome maintenance. We will pursue the following specific aims: First, we will characterize the role of essential genes in genome maintenance. Second, we will determine the enzyme-substrate relationship in the SUMO pathway, focusing on the function and substrates of SUMO-specific isopeptidase. Third, we will study how sumoylation of Mms21-specific substrates contribute to genome maintenance. In all of our studies, we will employ a combination of genetic, biochemical and proteomic approaches to study how the SUMO pathway specifically prevents duplication-mediated genome rearrangements, which are expected to provide new insights into the genetic basis of human cancers.

描述（由申请人提供）人类基因组包含许多“处于危险的”序列，这些序列容易受到突变，包括潜水员重复的序列，分段重复和拷贝数变化的区域。这种重复的序列元件可以通过非平行性同源重组（HR）引起基因组重排。已知许多人类疾病是由非平行性HR介导的染色体重排引起的。此外，许多癌症表现出正在进行的基因组重排，受到基因组中许多“处于危险”序列的刺激。酿酒酵母的酵母菌提供了一个强大的模型系统来研究基因组重排。尽管已经发现许多途径可以抑制基因组重排，但对重复介导的基因组重排的理解被特异性抑制仍然是基本的。 Sumoylation是一种进化配置的蛋白质翻译后修饰，众所周知，许多核活性包括基因转录，染色体分离，DNA复制和修复。我们已经发现了蛋白质Sumoylation在抑制重复介导的基因组重排方面的新功能，发现SUMO途径是迄今为止防止这种类型的基因组重排的最重要途径。在拟议的研究中，我们将表征相扑途径的遗传学和生物化学，重点是其在基因组维持中的功能。我们将追求以下特定目标：首先，我们将表征基因在基因组维持中的作用。其次，我们将确定SUMO途径中的酶基底关系，重点关注Sumo特异性异肽酶的功能和底物。第三，我们将研究MMS21特异性底物的Sumoylation如何有助于基因组维持。在我们的所有研究中，我们将采用遗传，生化和蛋白质组学方法的结合来研究SUMO途径如何明确防止重复介导的基因组重排，这些基因组重排有望为人类癌症的遗传基础提供新的见解。