Ribeiro-Silva, Cristina, Muniesa Vargas, Alba, Theil, Arjan, Davo Martinez, Carlota, Vermeulen, Wim, Lans, Hannes
[
International Worm Meeting,
2021]
Nucleotide excision repair (NER) is a major DNA repair pathway that removes a large variety of helix-distorting DNA damage. Hereditary mutations in NER genes that encode proteins that make up the core NER machinery, such in endonucleases XPF and XPG, can give rise to the cancer prone disorder xeroderma pigmentosum (XP) or to more severe disorders in which XP is combined with progressive neurodegeneration or progeroid Cockayne syndrome (CS) features, called XP-CS. Intriguingly, mutations in other factors of the core NER complex give rise to a milder phenotype. It is not properly understood why mutations in genes that act in the same DNA repair pathway cause different types of disease. Here, we use C. elegans as a model to study the phenotypic impact of different mutations in the evolutionary conserved NER pathway. We found that XPF-1 or XPG-1 deletion mutants show severe developmental arrest and neuronal dysfunction upon induction of UV damage. In the absence of XPF-1 or XPG-1, core NER-intermediates accumulate at DNA damage and stay stably bound to DNA. We hypothesized that this could shield the lesion from other DNA repair pathways and block transcription, which could cause this severe phenotype. Intriguingly, we found that inhibiting the binding of the core NER-intermediates to DNA in XPF-1 or XPG-1 worms alleviated the severe phenotype, confirming that the accumulation of repair intermediates can indeed be more toxic for cells than the damage itself. Together, these results strongly suggest that the persistence of NER intermediates adversely affects cell functionality, which may be a plausible explanation for why mutations in XPF or XPG can lead to more severe disease features than mutations in other core subunits.