PhD defence M. (Melanie) van der Woude

Below is a brief summary of the dissertation:

Safeguarding the structural and functional integrity of the genome is vital for sustaining life, , yet this is a constant challenge due to persistent DNA damage from both internal metabolic processes and external environmental factors. Failures in the pathways that ensure DNA repair and replication fidelity can lead to severe outcomes, including developmental and neurological disorders, cancer, and accelerated aging. To manage this, cells rely on the DNA damage response (DDR), a complex network that detects DNA damage, signals its presence, and coordinates appropriate repair mechanisms. Among these, nucleotide excision repair (NER) is critical for recognizing and removing bulky, helix-distorting lesions, particularly those caused by ultraviolet (UV) radiation. This thesis focuses in three research parts on the mechanisms that govern NER and the consequences of its dysfunction. It combines genetic, proteomic, cellular, and imaging-based methods using in vitro models and the model organism Caenorhabditis elegans. The first part presents novel experimental tools for studying NER. The second part centers on the TFIIH subunit TTDA (GTF-2H5). And the third part explores the molecular basis of various NER-related disorders, including xeroderma pigmentosum (XP), Cockayne syndrome (CS), XP-CS, and UV-sensitive syndrome (UVsS).