Analysis of the Replication Stress Response

复制压力响应分析

• 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
• 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

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.

项目总结