Transcription–replication conflicts underlie sensitivity to PARP inhibitors

Abstract An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers 1–6 . PARP inhibitors trap PARPs on DNA. The trapped PARPs are thought to block replisome progression, leading to formation of DNA double-strand breaks that require HR for repair 7 . Here we show that PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription–replication conflicts. Furthermore, the synthetic lethality of PARP inhibitors with HR deficiency is due to an inability to repair DNA damage caused by transcription–replication conflicts, rather than by trapped…

• NS
  National Science Foundation
• EC
  European Commission
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  Awards: 182487, 186230
• UD
  Université de Genève