Role of ATR in Cell Cycle Checkpoints

ATR 在细胞周期检查点中的作用

• 批准号: 7448492
• 负责人: William G Dunphy
• 金额: $ 44.6万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448492
• 关键词: Animals; Binding; Biological Models; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Nucleus; Cells; Chromatin; Chromosome abnormality; Collaborations; Complement; Complex; Coupled; Cyclin B; Cyclin-Dependent Kinases; Cyclins; DNA; DNA Damage; DNA Structure; DNA biosynthesis; DNA-dependent protein kinase; Eukaryotic Cell; Event; Genome; Genomics; Homologous Gene; Human; Laboratories; Maintenance; Maturation-Promoting Factor; Mitosis; Molecular; Pathway interactions; Phosphatidylinositols; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological Processes; Process; Protein Family; Protein Kinase; Proteins; Range; Regulation; Regulatory Pathway; Role; Site; Structure; System; Three Prime Repair Exonuclease 1; Vertebrates; Xenopus; base; egg; insight; member; novel; prevent; research study; response; sensor; ultraviolet damage

DESCRIPTION (provided by applicant): In eukaryotic cells, the Cdc2-cyclin B complex regulates the initiation of mitosis. Various checkpoint regulatory mechanisms prevent the entry into mitosis if the genome has not been replicated faithfully or has undergone various types of damage. In vertebrates, a pathway containing ATR, Claspin, and Chkl suppresses the activation of Cdc2-cyclin B when there is incompletely replicated or UV-damaged DNA in the nucleus. ATR is a member of the phosphatidylinositol kinase (PIK)-related family of proteins that also includes ATM and the DNA-dependent protein kinase (DNA-PK). ATR possesses a critical regulatory subunit called ATRIP (ATR-interacting protein). The ATR-dependent regulatory pathway can be studied effectively in cell-free extracts from Xenopus eggs. Xenopus homologues of ATR (Xatr) and ATRIP (Xatrip) have been cloned and characterized. Comprehensive studies of the structure, function, and regulation of Xatr-Xatrip will be conducted. The various functional domains of Xatr and Xatrip will be defined in order to understand how these proteins interact with one another. In addition, the mechanism by which Xatr-Xatrip associates with DNA will be analyzed. The Xatr-Xatrip complex undergoes activation upon binding to certain DNA structures. The mechanistic basis of this activation will be analyzed. For these studies, the role of phosphorylation in the regulation of Xatr-Xatrip will be examined. Moreover, searches for novel proteins that interact with Xatr-Xatrip to control its activation and/or action will be undertaken. To complement these efforts, the roles of known checkpoint proteins and replication proteins in the regulation of Xatr-Xatrip will be assessed. Finally, various screens for novel substrates of Xatr-Xatrip will be carried out. These studies may help to elucidate the range of physiological processes that are controlled by Xatr-Xatrip. It seems very likely that the ATR-ATRIP complex is necessary for the maintenance of genomic integrity in humans. Through the study of Xatr-Xatrip in a vertebrate system that is amenable to intensive functional analysis, important insights may be obtained into the mechanisms by which animal cells prevent the occurrence of chromosomal aberrations.

描述（由申请人提供）：在真核细胞中，Cdc2-Cyclin B复合物调节有丝分裂的起始。如果基因组尚未忠实复制或受到各种损害，则各种检查点调节机制可阻止进入有丝分裂。在脊椎动物中，当核中不完全复制或紫外线受损的DNA时，含有ATR，CLASPIN和CHKL的途径会抑制Cdc2-Cyclin B的激活。 ATR是磷脂酰肌醇激酶（PIK）相关的蛋白质家族的成员，该家族还包括ATM和DNA依赖性蛋白激酶（DNA-PK）。 ATR具有称为ATRIP（ATR-ATRETRACTING蛋白）的关键调节亚基。可以在异爪蟾卵中有效研究ATR依赖性调节途径。 ATR（XATR）和ATRIP（XATRIP）的Xenopus同源物已被克隆和表征。将对XATR-xatrip的结构，功能和调节进行全面研究。将定义XATR和XATRIP的各种功能域，以了解这些蛋白质如何相互作用。另外，将分析XATR-XATRIP与DNA相关的机制。 XATR-XATRIP复合物在与某些DNA结构结合后经历激活。将分析此激活的机械基础。对于这些研究，将研究磷酸化在XATR-xatrip调节中的作用。此外，将搜索与XATR-xatrip相互作用以控制其激活和/或作用的新型蛋白质。为了补充这些努力，将评估已知检查点蛋白和复制蛋白在XATR-xatrip调节中的作用。最后，将对XATR-XATRIP的新底物进行各种屏幕。这些研究可能有助于阐明由XATR-xatrip控制的生理过程范围。 ATR-ATRIP复合体似乎很可能是维持人类基因组完整性所必需的。通过对脊椎动物系统中XATR-XATRIP的研究，可以进行密集的功能分析，可以在动物细胞阻止发生染色体像差的机制中获得重要的见解。