Analysis of the Replication Stress Response

复制压力响应分析

基本信息

批准号：
10225410
负责人：
David K Cortez
金额：
$ 42.47万
依托单位：
VANDERBILT UNIVERSITY
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：
2015-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225410
关键词：
ATR checkpoint Affect Base Pairing Binding Biochemical Biochemical Genetics Cancer Etiology Cell Cycle Cells Cellular biology Chromatin Clinic Conflict (Psychology)DNA DNA Binding DNA Damage DNA Repair DNA biosynthesis DNA replication fork Disease Ensure Enzymes Failure Funding Genetic Screening Genetic Transcription Genome Genome Stability Genomic Instability Genomics Human Lesion Ligands Location Maintenance Malignant Neoplasms Modeling Motor Nature Outcome Pathway interactions Positioning Attribute Process Proteins Proteome Proteomics Reagent Replication-Associated Process Research Research Personnel Research Proposals SMARCA3 gene SS DNA BP Sequence Homology Signal Pathway Signal Transduction Single-Stranded DNA Site Speed Stress Testing Therapeutic Time Translating Work biological adaptation to stress cancer cell cancer therapy cell type chemotherapy clinical application endonuclease experimental study genetic approach genome integrity human disease improved inhibitor/antagonist insight prevent programs repaired replication stress response telomere tool

项目摘要

Project Summary Billions of base pairs of DNA must be replicated trillions of times during a human lifetime. Adding to the difficulty, replication is challenged by stresses including DNA template lesions, difficult to replicate sequences, and conflicts with transcription. Cells employ multiple repair and signaling responses to replication stress depending on the type, persistence, and location of the problem. We have employed proteomic and genetic approaches to understand how cells overcome replication stress. These analyses identified several new replication stress response proteins including RADX. RADX binds single-stranded DNA and prevents replication fork cleavage by endonucleases. We hypothesize that it regulates the processes of replication fork reversal and fork protection through its single-stranded DNA binding activity. We will test this hypothesis and more generally characterize mechanisms that regulate fork reversal and protection using biochemical and genetic approaches. Since cancer cells have elevated levels of replication stress and many cancer therapeutics work by interfering with DNA replication, these studies will also generate discoveries that may be translated into the cancer clinic.

项目概要在人的一生中，数十亿个 DNA 碱基对必须复制数万亿次。添加到困难，复制受到压力的挑战，包括 DNA 模板损伤、难以复制序列、并与转录发生冲突。细胞对复制应激采用多种修复和信号反应取决于问题的类型、持续性和位置。我们采用了蛋白质组学和遗传学了解细胞如何克服复制压力的方法。这些分析确定了一些新的复制应激反应蛋白，包括 RADX。 RADX 结合单链 DNA 并防止复制叉被核酸内切酶切割。我们假设它调节复制叉的过程通过其单链 DNA 结合活性实现逆转和分叉保护。我们将检验这个假设并更普遍地描述了使用生化和保护来调节叉逆转和保护的机制遗传方法。由于癌细胞的复制应激水平升高，许多癌症治疗方法通过干扰 DNA 复制来发挥作用，这些研究也将产生可能翻译成癌症诊所。