PhD defence M. (Marvin) van Toorn

Summary:

The hereditary information in our DNA lays at the heart of human physiology. However, genome integrity is continuously challenged by numerous sources of DNA damage, jeopardizing pivotal DNA-transacting processes such as transcription and replication. Multiple DNA repair pathways have evolved to counteract these detrimental effects of DNA damage, among which nucleotide excision repair (NER), which is specialized in removing a wide variety of helix-distorting DNA lesions. During NER, DNA lesions are first recognized, after which the lesions are verified, removed through dual incision and finally  the resulting single-stranded DNA gap is sealed through repair synthesis and ligation. Although the initial stages of NER are well understood, the factors involved in and the regulatory framework of later NER stages, especially after incision of the damaged DNA has taken place, remain poorly understood. In this thesis, we therefore focused on the regulation of these late steps of NER. We identified two new players in this process, HLTF and ATAD5-RLC, that facilitate efficient NER through removing specific repair intermediates. HLTF promotes the timely removal of the NER incision complex and incised damage-containing DNA after dual incision, whereas ATAD5-RLC is responsible for unloading the DNA clamp PCNA after repair synthesis. Our results thereby show that timely removal of repair intermediates crucially contributes to efficient DNA repair.