Impact of post-translational protein modifications on human cells with genome damage and cell transformation

Abstract

Individuals with Xeroderma Pigmentosum (XP), a rare autosomal genetic disease, present defects to repair DNA lesions induced by ultraviolet radiation (UV). As a consequence, XP patients are extremely sun sensitive and they have increased risk to develop Skin Cancer compared to the general population. A recent study has shown that UVA-irradiated XP variant (XP-V) cells present a slower DNA repair capacity and this is probably due to generation of Reactive Oxygen Species (ROS), causing the oxidation of DNA repair proteins. These results indicate an involvement of Post-Translational Modifications (PTMs) in DNA repair process. Although some PTMs have been demonstrated to be associated with DNA repair mechanisms, such as ubiquitination, phosphorylation and methylation, not much is known about the role of ROS-induced PTMs, namely oxidation and carbonylation, in this process. Besides these ROS-induced PTMs, the contribution of citrullination, a PTM involved in chromatin condensation and decondensation, and therefore DNA availability to be repaired after UV-induced DNA damage, has not been studied in DNA damage and repair. In this project, we aim to investigate in detail the participation of the PTMs oxidation, carbonylation and citrullination in the DNA repair process and whether PTMs of DNA repair proteins can decrease efficiency of repair mechanisms, increasing DNA damage, mutagenesis and carcinogenesis. Moreover, we want to evaluate whether XP cells present an increased malignant transformation ability, as expected from the clinical phenotype of the patients. For that, we plan to optimize a protocol to select malignant transformed cells from XP patients and perform exome sequencing of the selected clones. (AU)