Dissertation

New dimensions of the cellular response to DNA damage

Thirty years ago, mutations in the BRCA1 gene were first linked to hereditary breast and ovarian cancer, establishing a genetic basis for cancer development.

Author: S.C. Moser
Date: 14 November 2025
Links: Thesis in Leiden Repository

BRCA1 was soon recognized as essential for repairing DNA double-strand breaks through homologous recombination (HR), a process critical for maintaining genome stability. This thesis investigates the mechanistic underpinnings of HR and evaluates therapeutic strategies for HR-deficient cancers, including platinum-based chemotherapy and PARP inhibitors (PARPi), while proposing approaches to overcome therapy resistance.We explore the poorly understood late stages of HR, identifying FIRRM as a crucial factor in resolving HR intermediates. Loss of FIRRM causes sensitivity to DNA-damaging agents, chromosomal instability, and accelerated tumorigenesis, suggesting its role as a predictor of therapy response. Furthermore we examine biomarkers of HR deficiency in triple-negative breast cancer, showing that shallow genome sequencing effectively predicts platinum sensitivity and identifying XRCC3 and ORC1 mutations as novel predictors. We review PARPi therapy, resistance mechanisms, and strategies to enhance efficacy. Finally, we revealed that PARPi disrupt chromatin by evicting histones, a process mediated by NASP and PARP1, and demonstrates that targeting histone supply pathways increases PARPi sensitivity. The thesis concludes by highlighting future directions to advance synthetic lethality strategies against HR-deficient tumors.