Origin firing at repetitive sequences and genome replication

重复序列和基因组复制的起源

• 批准号: 9008959
• 负责人: Antonio Bedalov
• 金额: $ 47.23万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008959
• 关键词: Address; Affect; Age; Aging; Biological Assay; Biological Phenomena; Caloric Restriction; Cell Aging; Cell Cycle; Cells; Chromatin; Chromosome Structures; Complex; DNA; DNA biosynthesis; Data; Elements; Enzymes; Event; G1 Phase; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Genomics; Genotype; Health; Heterochromatin; Histone Deacetylase; Human; Human Genome; Lead; Licensing; Light; Location; Longevity; Malignant Neoplasms; Methods; Modeling; Molecular; Monitor; Mothers; Mutation; Nature; Nucleosomes; Nucleotides; Nutritional; Nutritional status; Pathway interactions; Peptide Initiation Factors; Phase; Plasmids; Positioning Attribute; Proteins; Recruitment Activity; Repetitive Sequence; Replication Initiation; Replication Origin; Repression; Resolution; Resources; Rest; Ribosomal DNA; Role; Saccharomyces cerevisiae; Saccharomycetales; Shapes; Specificity; System; Tandem Repeat Sequences; Temperature; Testing; Time; Trans-Activators; Variant; Work; Xenopus; Yeasts; carcinogenesis; chromatin remodeling; deep sequencing; environmental change; epigenome; epigenomics; gel electrophoresis; genome-wide; insight; research study; tool

DESCRIPTION (provided by applicant) Over half of the human genome is comprised of repetitive DNA organized as gene-poor, late replicating, transcriptionally silent heterochromatin. Recent studies suggest that there is a widespread opening of chromatin at repeated regions during carcinogenesis and aging. Given the total amount of repetitive DNA and the tendency of sequences in open chromatin to more readily serve as replication origins, these chromatin changes could significantly perturb global genome replication by outcompeting other regions of the genome for limiting replication factors. Indeed, our data from budding yeast suggest that increasing the efficiency of origin firing at repetitive sequences impairs DNA replication across the genome. In this proposal we use Saccharomyces cerevisiae to test our model that nucleosome re-positioning promotes the recruitment of initiation factors to replication origins in repetitive sequences and furthermore, that activation of origins in these repetitive sequences compromises the replication and stability of unique portions of the genome. S. cerevisiae is an excellent system in which to perform these tests: the major repetitive sequence, the ribosomal DNA (rDNA) is composed of homogenous tandem repeats (150 copies), each containing a potential origin of replication whose function is sensitive to chromatin context. Moreover, the sequence specificity of yeast origins creates uniform and predictable positioning of replication initiation factors and nucleosomes in their vicinity, greatly facilitating application and interpretation of a deep sequencing method for epigenomic profiling that we have developed. Our results will provide insights into the mechanisms by which chromatin and nucleosome positioning modulate replication origins at repetitive sequences and will shed light on the largely unexplored phenomenon of intra-genomic competition for replication resources as a mechanism that shapes global replication.

DESCRIPTION（由申请人提供）