DNA damage response and repair of a broken chromosome

DNA 损伤反应和断裂染色体的修复

• 批准号: 10403563
• 负责人: JAMES E HABER
• 金额: $ 94.5万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403563
• 关键词: Affect; Animal Model; Area; Autophagocytosis; Biochemistry; Biological Models; Cell Cycle Arrest; Cell Cycle Progression; Cells; Chromatin; Chromosomes; Complex; DNA Damage; DNA Repair; DNA damage checkpoint; Double Strand Break Repair; Event; Funding; Genes; Genetic Recombination; Genomic Instability; Goals; Hand; Human; Malignant Neoplasms; Mammalian Cell; Molecular; Monitor; Mutation; National Institute of General Medical Sciences; Process; Research; Saccharomycetales; Signal Transduction; Single-Stranded DNA; Site; base; cancer cell; homologous recombination; in vivo; insight; repaired; response

Project Summary The overall goal of NIGMS-funded research in my lab is to describe the molecular and cellular mechanisms by which cells sense the presence of DNA damage and carry our repair of chromosomal double-strand breaks (DSBs). Using budding yeast as a model system, it is possible to induce site-specific DSBs with a high degree of synchrony not yet possible in mammalian cells, allowing “in vivo biochemistry” approaches to monitor intermediate steps in DSB repair and DNA damage signaling. The first of three foci of this proposal investigates key questions concerning DSB repair by homologous recombination. How are homologous donor sequences found and used to repair a DSB? How are mismatches tolerated and repaired during different steps of recombination? How do cells deal with chromatin during repair and how is chromatin re- established after repair is complete? And how is gene editing accomplished using single-stranded DNA templates? The second area seeks to understand what is the basis of the 1000-fold increase in mutations associated with DSB repair and how microhomologies are used in repair-dependent template switching, creating complex chromosome rearrangements analogous to events recently found in human cancers. The third main objective is to understand how the DNA damage checkpoint and DNA damage-induced autophagy are regulated. We wish to determine: How does the DNA damage response affect DSB repair? How is the DNA damage checkpoint maintained and how is autophosphorylation of Mec1ATR regulated? What is the basis of a regulatory hand-off between the damage response and the spindle assembly checkpoint? Finally, we will determine the targets of DNA damage-induced autophagy and how autophagy contributes to cell cycle arrest in response to even a single unrepaired DSB. These studies will provide new insights and guidance in defining the DSB repair and checkpoint signaling in human cells.

项目总结