Ubiquitination in the UV-induced DNA Damage Response: from proteomics to patient

Abstract

The integrity of DNA is continuously challenged by genotoxic agents from both internal and external origin that severely hamper vital DNA-dependent processes as genome duplication by replication and reading of the genetic code by transcription. The adverse effects of DNA damage are counteracted by a complex network of genome defence processes, referred to as the DNA damage response (DDR), which consists of different dedicated DNA repair systems and signalling pathways. Nucleotide excision repair (NER) is the main DNA repair process in mammalian cells that removes UV-induced DNA lesions. Protein ubiquitination has emerged as a key regulatory mechanism for this pathway. However, how the entire UV-light induced DDR (UV-DDR) is controlled via ubiquitination remains largely unknown. The aim of the research described in this thesis is to better understand the ubiquitin-mediated regulation of the UV-DDR. To identify new ubiquitin modifications and proteins not previously known to be involved within the UV-DDR on a proteome-wide scale mass spectrometry (MS) was used. To provide the necessary background Chapter 1 summarizes the current knowledge on DDR, ubiquitination and MS-based methods.