Transcription-replication conflicts underlie sensitivity to PARP inhibitors

  • Nature. 2024 Apr;628(8007):433-441. doi: 10.1038/s41586-024-07217-2.
Michalis Petropoulos  1 ,  Angeliki Karamichali  #  1 ,  Giacomo G Rossetti  #  2 ,  Alena Freudenmann  2  3 ,  Luca G Iacovino  2 ,  Vasilis S Dionellis  1 ,  Sotirios K Sotiriou  2  3 ,  Thanos D Halazonetis  4
Affiliations
  • 1. Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland.
  • 2. FoRx Therapeutics AG, Basel, Switzerland.
  • 3. Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
  • 4. Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. [email protected].
  • # Contributed equally.
PMID: 38509368 DOI: 10.1038/s41586-024-07217-2
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 cancers1-6. 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 repair7. 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 PARPs. Along these lines, inhibiting transcription elongation in early S phase rendered HR-deficient cells resistant to PARP inhibitors and depleting PARP1 by small-interfering RNA was synthetic lethal with HR deficiency. Thus, inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in HR-deficient settings.