Genome instability induced by homologous recombination

同源重组引起的基因组不稳定

基本信息

批准号：
10795314
负责人：
Wolf-Dietrich Heyer
金额：
$ 1.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10795314
关键词：
Abbreviations Affect Alleles Architecture Base Pairing Biochemical Biological Assay Biological Models Cell Death Chromosomal Instability Chromosomal Rearrangement Chromosome Segregation Chromosomes Complex Copy Number Polymorphism Cruciform DNA DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Sequence DNA lesion DNA replication fork Development Double Minutes Event Evolution Fertility Filament Genetic Genetic Recombination Genome Genome Stability Genomic Instability Genomic approach Goals Human Invaded Ionizing radiation Joints Location Maintenance Malignant Neoplasms Mediating Meiosis Meiotic Recombination Modality Modeling Molecular Mutation Nonhomologous DNA End Joining Nuclear Outcome Pathway interactions Pattern Point Mutation Positioning Attribute Process Quality Control Rad51 recombinase Reaction Recovery Research Saccharomyces cerevisiae Saccharomycetales Shapes Single-Stranded DNA Somatic Cell Syndrome Testing Tumor Suppressor Proteins Variant Work cancer genome cancer therapy chromatin immunoprecipitation chromothripsis cofactor design genetic approach genome-wide homologous recombination human disease improved in vivo model organism novel repaired restraint tumorigenesis

项目摘要

Project Summary The general goal of the proposed research is to define the pathways and their mechanisms by which homologous recombination contributes to genome instability in somatic cells through events involving repeated DNA sequences. Using the budding yeast Saccharomyces cerevisiae as a model organism we will define the mutational signatures of multi-invasion-induced rearrangements, which are induced by a single Rad51-ssDNA filament simultaneously pairing with repeated DNA sequences on different chromosomes or locations on a single chromosome. The aims are designed to establish novel mechanisms and paradigms that are applicable to central questions concerning genomic stability and genome maintenance. We will establish novel mutational signatures caused by homologous recombination that will help to define the mechanism underlying such signatures found in humans, including cancer genomes. Moreover, our work will contribute to understanding the mechanisms underlying major processes that shape genomes during ontogenic development and evolution, including non-allelic homologous recombination, insertions, mutation showers (kataegis), double minute chromosome formation, and chromosome instability syndromes such as chromothripsis. The Specific Aims are: (1) Determine the genetic consequences of multi-invasion-induced genome rearrangements. and (2) Identify pathways that affect multi-invasions and the genome-wide search for homology. Both aims require the use of the table-top centrifuge requested in this application.

项目概要拟议研究的总体目标是定义途径及其机制同源重组通过涉及重复的事件导致体细胞基因组不稳定 DNA 序列。使用芽殖酵母酿酒酵母作为模式生物，我们将定义由单个 Rad51-ssDNA 诱导的多重入侵诱导重排的突变特征丝同时与不同染色体上或不同位置上的重复DNA序列配对单染色体。目标旨在建立适用的新颖机制和范例有关基因组稳定性和基因组维护的核心问题。我们将建立新的突变由同源重组引起的签名将有助于定义这种机制的基础在人类中发现的特征，包括癌症基因组。此外，我们的工作将有助于理解在个体发育过程中塑造基因组的主要过程的潜在机制进化，包括非等位基因同源重组、插入、突变簇（kataegis）、双微小染色体形成和染色体不稳定综合征，例如染色体碎裂。具体目的是：（1）确定多次入侵诱导的基因组重排的遗传后果。和（2）确定影响多重入侵和全基因组同源性搜索的途径。这两个目标都需要使用本申请中要求的台式离心机。