Aurora B kinase is the downstream target of ATR

Aurora B 激酶是 ATR 的下游靶点

• 批准号: 6999573
• 负责人: BILL H CHANG
• 金额: $ 5.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999573
• 关键词: DNA replication; DNA replication origin; HeLa cells; SDS polyacrylamide gel electrophoresis; ataxia telangiectasia; chromosome disorders; chromosome movement; enzyme activity; histones; immunocytochemistry; neoplastic process; phosphatidylinositols; phosphorylation; postdoctoral investigator; protein structure function; serine threonine protein kinase

DESCRIPTION (provided by applicant): Disruptions in accurate DNA replication and segregation during the cell cycle results in genomic instability and missegregation of chromosomes. Genomic instability has long been recognized as an important step in converting normal cells into neoplastic cells. Recently, an abnormal chromosomal phenotype has been described whereby there is a delay in the replication timing (DRT) of an entire chromosome. Chromosomes with DRT have been shown to be unstable and contribute to genomic instability. DRT chromosomes show a delay in the mitosis-specific phosphorylation of histone H-3 on serine 10 and a delay in mitotic chromosome condensation (DMC). H-3 phosphorylation has been shown to be an important step in chromosome condensation and segregation. Aurora B kinase is thought to be responsible for the phosphorylation of H-3. Recent results from the Thayer lab have shown that DRT chromosomes activate the replication checkpoint pathway via ATR. Therefore, I hypothesize that inhibition of Aurora B, either by inhibition of kinase activity or inhibition of recruitment to the chromosome, plays a direct role in the DMC phenotype. The objective is to characterize the link between DRT/DMC, the replication checkpoint, and Aurora B kinase.

描述（由申请人提供）：细胞周期期间准确的DNA复制和隔离的破坏会导致基因组不稳定性和染色体的错误隔离。长期以来，基因组不稳定性被认为是将正常细胞转化为肿瘤细胞的重要步骤。最近，已经描述了一个异常的染色体表型，从而延迟了整个染色体的复制时机（DRT）。带有DRT的染色体已被证明是不稳定的，并导致基因组不稳定性。 DRT染色体显示出丝氨酸10组蛋白H-3的有丝分裂特异性磷酸化和有丝分裂染色体凝结（DMC）的延迟。 H-3磷酸化已被证明是染色体凝结和分离的重要步骤。 Aurora B激酶被认为是H-3的磷酸化的原因。 Thayer Lab的最新结果表明，DRT染色体通过ATR激活复制检查点途径。因此，我假设通过抑制激酶活性或抑制染色体募集的抑制Aurora B，在DMC表型中起着直接的作用。目的是表征DRT/DMC，复制检查点和Aurora B激酶之间的链接。