DNA-embedded ribonucleotides: from mechanistic insights to therapeutic opportunities

DNA-embedded ribonucleotides: from mechanistic insights to therapeutic opportunities

Maintenance of genome integrity is of fundamental importance for cell survival and proliferation. It is also vital for counteracting disease, as genome instability is a hallmark of cancer, developmental defects, premature ageing and inflammation. Ribonucleotides are the most abundant non-canonical nucleotides in the mammalian genome, with over 1 million DNA-embedded ribonucleotides per replicating cell, posing a significant challenge to genome stability. Ribonucleotides incorporated during DNA replication are normally removed by Ribonuclease (RNase) H2, a developmentally essential enzyme that initiates error-free ribonucleotide excision repair (RER).

In this talk, I will present our recent findings that shed light on the molecular mechanisms of genome instability caused by aberrant processing 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 RNase H2 leads to synthetic lethality with PARP inhibitors, small molecule inhibitors with proven efficacy in targeting homologous recombination (HR)-deficient cancers. RNASEH2B is frequently deleted in chronic lymphocytic leukaemia and metastatic prostate cancer and its collateral loss enhances vulnerability of cancer cells to PARP inhibitors. I will discuss how synthetic lethality between RER deficiency, which is mechanistically distinct from HR deficiency, and PARP inhibition could be exploited therapeutically.

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