The genetic and biochemical basis of leading strand synthesis and PARP inhibitors sensitivity

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• Roberto Bellelli
• Tuesday 13 May 2025, 12:00-13:00
• Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.

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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) sensitizes cancer cells to PAR Pi 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 synthetic 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. Consistently with loss of Pole processivity being crucial for sensitization to PAR Pi, we further show that deletion of CHTF18 sensitizes cancer cells to PAR Pi 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.

This talk is part of the Department of Biochemistry - Tea Club Seminars series.

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