Xeroderma pigmentosum (XP) is a rare genetic disorder of nucleotide excision repair (NER). XP is classified into eight complementation groups, XP-A to XP-G and V, depending on the protein component of the NER pathway that is defective. NER is split into two branches. Transcription coupled repair (TC-NER), which rapidly repairs DNA damage on the transcribed strand of actively transcribed regions of DNA. Global genome NER (GG-NER) is a slower process that repairs DNA damage on non-transcribed strands. Patients with defective NER are unable to repair Ultraviolet (UV) induced DNA damage. The somatic mutations not repaired cause the characteristic features of 10,000-fold increased risk of skin cancer, internal malignancies and neurodegeneration. Neurodegeneration occurs in patients with deficient TC-NER (complementation groups A, D, F and G). Since UV radiation does not reach the brain, the neurological disease in XP is thought to be the result of DNA damage that is normally repaired by NER, however the exact cause of neurodegeneration is not understood.

In this thesis, I set out to understand the biological processes underlying neurodegeneration in XP. I studied multiple patients from a variety of complementation groups using a human induced pluripotent stem (hiPSC) model. Functional multi-omic characterisation at several stages of the directed differentiation of hiPSCs into neurons revealed an elevated endoplasmic reticulum stress response and dysfunction of the ubiquitin proteasome system (UPS) in XP neuronal models. I have also demonstrated an accumulation of multiple oxidised nucleosides, implicating oxidative stress as a contributing factor to the disease process. This study demonstrates that such hiPSC systems can be used to successfully model XP and collectively these findings offer new insights into the pathogenesis of neurodegeneration in XP. In the future, these results can be validated in patient-derived samples held in national brain biobanks and we can further explore these implicated pathways with the aim to determine how mutations in genes of the NER pathway result in the findings of this thesis.

I have also explored the mutational signatures observed in XP and I present a case study of the clinical applications of WGS in an XP patient with metastatic angiosarcoma.