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 DNA 精确复制和分离的破坏会导致基因组不稳定和染色体错误分离。基因组不稳定性长期以来被认为是将正常细胞转化为肿瘤细胞的重要步骤。最近，已经描述了一种异常染色体表型，即整个染色体的复制计时（DRT）延迟。经 DRT 处理的染色体已被证明不稳定并导致基因组不稳定。 DRT 染色体显示组蛋白 H-3 在丝氨酸 10 上的有丝分裂特异性磷酸化延迟以及有丝分裂染色体浓缩 (DMC) 延迟。 H-3 磷酸化已被证明是染色体浓缩和分离的重要步骤。 Aurora B 激酶被认为负责 H-3 的磷酸化。 Thayer 实验室的最新结果表明，DRT 染色体通过 ATR 激活复制检查点途径。因此，我推测 Aurora B 的抑制（通过抑制激酶活性或抑制染色体募集）在 DMC 表型中发挥直接作用。目的是表征 DRT/DMC、复制检查点和 Aurora B 激酶之间的联系。