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SUMMARY:The genetic and biochemical basis of leading strand synthesis and 
 PARP inhibitors sensitivity - Roberto Bellelli 
DTSTART:20250513T110000Z
DTEND:20250513T120000Z
UID:TALK226474@talks.cam.ac.uk
CONTACT:90994
DESCRIPTION:Genomic instability is a hallmark of cancer and understanding 
 its nature has provided avenues for cancer therapy. The most prominent exa
 mple 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 PARP
 i by unleashing replicative gap accumulation (Hill\, Ozgencil et al.\, Cel
 l 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 de
 letion of a series of iron metabolism genes and components of the CHTF18-R
 FC2/5 complex. By combining cell biology\, structural modelling and bioche
 mistry\, we define the existence of two tiers of regulation of Pole proces
 sivity: leading strand-specific loading of PCNA by CHTF18-RFC2/5 and “gr
 ipping” of newly synthesised dsDNA by POLE3-POLE4. Consistently with los
 s of Pole processivity being crucial for sensitization to PARPi\, we furth
 er show that deletion of CHTF18 sensitizes cancer cells to PARPi by promot
 ing replicative gap accumulation. Thus\, POLE3-POLE4 and CHTF18-RFC2/5 rep
 resent two essential “tiers” required to maintain Pole processivity an
 d prevent replicative gap accumulation.
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Tennis Court Road
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