Because the integrity of DNA is critical to the health of the cell, there are many pathways involved in repairing damage to it. Since 2005, a paradigm has emerged that drugs that target DNA repair factors, particularly in cells already defective in another DNA repair pathway, had therapeutic promise. PARP inhibitors have been thought to stall DNA replication, and therefore cause genome instability. Jiri Bartek and colleagues now show that, in fact, PARP inhibition accelerates replication fork speed and induces DNA damage because the damage is not recognized. These results offer a new perspective on the mechanism by which inhibition of PARP can enhance therapeutic treatments.
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