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SUMMARY:DNA-embedded ribonucleotides: from mechanistic insights to therape
 utic opportunities  - Dr Olga Murina\; MRC Institute of Genetics and Molec
 ular Medicine\, University of Edinburgh
DTSTART:20200306T120000Z
DTEND:20200306T130000Z
UID:TALK139309@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Maintenance of genome integrity is of fundamental importance f
 or cell survival and proliferation. It is also vital for counteracting dis
 ease\, as genome instability is a hallmark of cancer\, developmental defec
 ts\, premature ageing and inflammation. Ribonucleotides are the most abund
 ant non-canonical nucleotides in the mammalian genome\, with over 1 millio
 n DNA-embedded ribonucleotides per replicating cell\, posing a significant
  challenge to genome stability. Ribonucleotides incorporated during DNA re
 plication are normally removed by Ribonuclease (RNase) H2\, a developmenta
 lly essential enzyme that initiates error-free ribonucleotide excision rep
 air (RER). In this talk\, I will present our recent findings that shed lig
 ht on the molecular mechanisms of genome instability caused by aberrant pr
 ocessing of DNA-embedded ribonucleotides in mammalian cells. Using genome-
 wide CRISPR/Cas9 screens we have also established\, in collaboration with 
 the Durocher laboratory (University of Toronto)\, that deficiency for RNas
 e H2 leads to synthetic lethality with PARP inhibitors\, small molecule in
 hibitors with proven efficacy in targeting homologous recombination (HR)-d
 eficient cancers. RNASEH2B is frequently deleted in chronic lymphocytic le
 ukaemia and metastatic prostate cancer and its collateral loss enhances vu
 lnerability of cancer cells to PARP inhibitors. I will discuss how synthet
 ic lethality between RER deficiency\, which is mechanistically distinct fr
 om HR deficiency\, and PARP inhibition could be exploited therapeutically.
  
LOCATION:Babraham - The Cambridge Building - Kings Hedges Room
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