Post-translational modifications in the dna damage response

Abstract

Post-translational modifications (PTMs) play essential roles in gene regulation, cellular function, tissue development and metabolism, in which they can be critical for protein function, by influencing their localization, stability, activity and interaction with other molecules. In particular, the cellular responses to DNA damage involves conserved mechanisms of recruitment, precise control of protein levels and activation of the numerous proteins involved, events for which a multitude of PTMs are required. A correct DNA damage response (DDR) is essential in maintaining genome integrity and abnormalities in this process can lead to developmental defects, genetic diseases, premature aging and cancer. This is underscored by the observation of signs of replication stress and an activated DDR during the early stages of tumorigenesis. On the other hand, DNA damaging agents are widely used in cancer treatments, due to their toxicity for proliferating cells. Studying the mechanistic details of genome stability, and the role of PTMs in this response, is therefore crucial for the development of therapies against cancer. Moreover, all these modifications are carried out by enzymes and can therefore potentially be inhibited. As a result, regulating these modifications could have a therapeutic impact. In this thesis we identified four novel enzymes regulating PTMs that are involved in maintaining genome integrity. This knowledge could be used in the future to understand the process of tumorigeneses and might help to improve cancer treatments.