Signal rewiring of the DNA damage pathway in cancer

“DNA损伤反应通路在细胞中是必不可少的，以防止遗传不稳定和导致癌症的突变的积累。Chk2是一种丝氨酸-苏氨酸激酶，响应DNA损伤而被激活，并通过下游蛋白的磷酸化来传递细胞周期停滞、衰老或凋亡的信号。Chk2激活环中的一个突变K373E已被确定为几种癌症类型中的一种反复突变，主要在肺癌和结直肠癌中。然而，这种突变引起的变化尚未确定。我们假设Chk2K373E的突变导致下游信号通路的重新连接，这可能会发现新的治疗机会和可操作的靶点。将使用细胞模型和体外激酶分析来研究K373E突变对DNA损伤反应中Chk2激酶活性和下游磷酸化信号的影响。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。

"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."