Function of the ATR-ATRIP complex

ATR-ATRIP 复合物的功能

• 批准号: 8967327
• 负责人: David K Cortez
• 金额: $ 1.14万
• 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: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967327
• 关键词: ATM Signaling Pathway; ATM function; Acute; Antineoplastic Agents; Binding; Biochemical; Biochemical Genetics; CHES1 gene; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Survival; Cells; Cellular biology; Clinic; Complex; DNA; DNA Damage; DNA Replication Damage; DNA biosynthesis; Data; Data Set; Drug Targeting; Event; Exhibits; Funding; Genes; Genetic Screening; Genome; Genomics; Goals; Knowledge; Maintenance; Malignant Neoplasms; Mining; Modeling; Mutation; Nature; Normal Cell; Nucleotides; Oncogenes; Outcome; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Positioning Attribute; Proteins; RNA; Recruitment Activity; Regulation; Research; Research Personnel; Research Proposals; Signal Pathway; Signal Transduction; Single-Stranded DNA; Stress; TOPBP1 Gene; TREX1 gene; Testing; Work; base; biological adaptation to stress; cancer cell; carcinogenesis; genetic approach; genome integrity; helicase; inhibitor/antagonist; innovation; phrases; prevent; protein function; public health relevance; repaired; replication factor A; response; targeted cancer therapy

Project Summary The long-term goal of the proposed research is to understand how cells preserve genome integrity during DNA replication. Specifically, this application focuses on the ATR (ATM and rad3-related) signaling pathway. ATR functions at the apex of a DNA damage and replication stress response pathway that is needed every cell division cycle to promote the complete and accurate replication of the genome. Many cancer cells are highly dependent on ATR function for proliferation and viability because of elevated levels of oncogene-induced replication stress and mutations in other genome maintenance pathways. Thus, ATR may be a useful drug target based on a synthetic lethal approach. In this proposal we test a specific model of how ATR promotes replication fork stabilization and repair, define the consequences of acute ATR inhibition on DNA replication and cell fate outcomes, define and characterize new ATR-regulated proteins that act at damaged replication forks, characterize cancer settings in which ATR inhibition might be useful using synthetic lethality, and test a new model of how ATR is regulated by autophosphorylation. This is a focused proposal aimed at understanding the most important and least understood aspects of ATR function. Specific hypotheses and innovative concepts based on preliminary data are tested using advanced biochemical and genetic approaches. In addition, the aims provide opportunities for unexpected discoveries about the mechanisms that maintain the genome during DNA replication and when ATR pathway inhibitors may be useful in the cancer clinic.

项目总结