Speaker: Roberto Bellelli - Barts Cancer Institute
Date: 13 May
Time: 12:00pm
Venue: Jean Thomas Lecture Theatre
Abstract:
Genomic instability is a hallmark of cancer and understanding its nature has provided avenues for cancer therapy. The most prominent example has been the successful use of PARP inhibitors (PARPi) in BRCA1/BRCA2-mutated cancers. We have recently discovered that loss of the POLE3-POLE4 subunits of DNA Polymerase Epsilon (Pole) sensitises cancer cells to PARPi by unleashing replicative gap accumulation (Hill, Ozgencil et al., Cell Reports 2024). By performing a genome-wide CRISPR screening in POLE4 KO cells, we now show that loss of POLE3-POLE4 is synthetically lethal with deletion of a series of iron metabolism genes and components of the CHTF18-RFC2/5 complex. By combining cell biology, structural modelling and biochemistry, we define the existence of two tiers of regulation of Pole processivity: leading strand-specific loading of PCNA by CHTF18-RFC2/5 and “gripping” of newly synthesised dsDNA by POLE3-POLE4. Consistent with the loss of Pole processivity being crucial for sensitisation to PARPi, we further show that deletion of CHTF18 sensitises cancer cells to PARPi by promoting replicative gap accumulation. Thus, POLE3-POLE4 and CHTF18-RFC2/5 represent two essential “tiers” required to maintain Pole processivity and prevent replicative gap accumulation.