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CATEGORIES:Biochemistry Seminar Series - External Speakers
SUMMARY:The genetic and biochemical basis of leading stran
 d synthesis and PARP inhibitors sensitivity - Robe
 rto Bellelli 
DTSTART;TZID=Europe/London:20250513T120000
DTEND;TZID=Europe/London:20250513T130000
UID:TALK226474AThttp://talks.cam.ac.uk
URL:http://talks.cam.ac.uk/talk/index/226474
DESCRIPTION:Genomic instability is a hallmark of cancer and un
 derstanding its nature has provided avenues for ca
 ncer therapy. The most prominent example has been 
 the successful use of PARP inhibitors (PARPi) in B
 RCA1/BRCA2-mutated cancers. We have recently disco
 vered that loss of the POLE3-POLE4 subunits of DNA
  Polymerase Epsilon (Pole) sensitizes cancer cells
  to PARPi by unleashing replicative gap accumulati
 on (Hill\, Ozgencil et al.\, Cell Reports 2024).  
 By performing a genome-wide CRISPR screening in PO
 LE4 KO cells\,  we now show that loss of POLE3-POL
 E4 is synthetic lethal with deletion of a series o
 f iron metabolism genes and components of the CHTF
 18-RFC2/5 complex. By combining cell biology\, str
 uctural modelling and biochemistry\, we define the
  existence of two tiers of regulation of Pole proc
 essivity: leading strand-specific loading of PCNA 
 by CHTF18-RFC2/5 and “gripping” of newly synthesis
 ed dsDNA by POLE3-POLE4. Consistently with loss of
  Pole processivity being crucial for sensitization
  to PARPi\, we further show that deletion of CHTF1
 8 sensitizes cancer cells to PARPi by promoting re
 plicative gap accumulation. Thus\, POLE3-POLE4 and
  CHTF18-RFC2/5 represent two essential “tiers” req
 uired to maintain Pole processivity and prevent re
 plicative gap accumulation.
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Te
 nnis Court Road
CONTACT:
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