Signal rewiring of the DNA damage pathway in cancer

癌症中 DNA 损伤途径的信号重新布线

• 批准号: 2771579
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2771579
• 关键词: Signal; rewiring; DNA; damage; pathway

"The DNA damage response pathway is essential in cells to prevent genetic instability and the build-up of mutations, which lead to cancer. CHK2 is a serine-threonine kinase activated in response to DNA damage and acts through phosphorylation of downstream proteins to signal for cell cycle arrest, senescence, or apoptosis. A mutation in the activation loop of CHK2, K373E, has been identified as a recurrent mutation in several cancer types, predominantly in lung and colorectal cancer. However, the changes caused by this mutation are yet to be established. We hypothesise that mutation of CHK2 K373E results in rewiring of downstream signalling pathways which may uncover new therapeutic opportunities and actionable targets. Cellular models and in vitro kinase assays will be used to investigate the effect of the K373E mutation on CHK2 kinase activity and downstream phospho-signalling in response to DNA damage. This will give insight into how activation loop mutations of kinases can change substrate specificity and reveal the disease-associated changes in CHK2."

“在细胞中，DNA损伤反应途径对于防止导致癌症的遗传不稳定和突变的积累至关重要。CHK2是一种丝氨酸-苏氨酸激酶，在DNA损伤时被激活，并通过下游蛋白的磷酸化作用，发出细胞周期阻滞、衰老或凋亡的信号。CHK2激活环中的突变K373E已被确定为几种癌症类型的复发突变，主要是肺癌和结直肠癌。然而，这种突变引起的变化尚未确定。我们假设CHK2 K373E突变导致下游信号通路的重新布线，这可能会发现新的治疗机会和可操作的靶点。细胞模型和体外激酶实验将用于研究K373E突变对CHK2激酶活性和下游磷酸化信号在DNA损伤响应中的影响。这将深入了解激酶的激活环突变如何改变底物特异性，并揭示CHK2中与疾病相关的变化。”