Signal rewiring of the DNA damage pathway in cancer

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"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."