Meneguello, Leticia; (2024) Investigating tolerance mechanisms to oncogene-induced genome instability. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis_LeticiaMeneguello.pdf - Accepted Version Access restricted to UCL open access staff until 1 September 2027. Download (50MB)

Abstract

Cancer is a collection of diseases in which cells undergo continued proliferation, often driven by oncogenic activity. Enhanced levels of oncogene-induced proliferation can lead to inefficient DNA replication and high levels of DNA replication stress, known as Oncogene-induced replication stress. Oncogene-induced replication stress can cause DNA damage identified in precancerous lesions and is believed to be an important source of genome instability, contributing to cancer onset and evolution. The cellular response to replication stress limits the accumulation of replication stress-induced DNA damage and is thought to be essential for cancer cell survival, providing a promising target for cancer therapy. Therefore, the replication stress response is central to cancer biology and its treatment. This project aimed to identify and characterise potential novel factors involved in the replication stress response, which could be targeted to inhibit cancer cell tolerance to replication stress. By validating hits from an imaging-based screen, I identified the protein RNA Exonuclease 1 Homolog (REXO1), a poorly explored exonuclease, as a novel player in the tolerance mechanism to oncogene-induced genome instability. My work demonstrates REXO1 dependency for genome stability in cells experiencing oncogenic activity that accelerates S-phase entry, such as c-Myc and Cyclin E. It also reveals a role for REXO1 in R-loop metabolism. R-loops are hybrid DNA/RNA structures formed upon transcription perturbation and a source of replication stress and genome instability. Loss of REXO1 causes an accumulation of R-loops, suggesting a direct role in preventing the formation or promoting the repair of these structures. Finally, this work also shows that REXO1 enzymatic activity can degrade DNA/RNA hybrids. This identifies REXO1 as a novel player in R-loop homeostasis and indicates a possible mechanism by which REXO1 prevents genomic instability. Further investigation is required to establish the role of REXO1 in cancer and the prospect of targeting R-loop proteins in cancer therapy.

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