Transcription-replication conflicts underlie sensitivity to PARP inhibitors

• 成果类型: Article
• 署名作者: Petropoulos, Michalis; Karamichali, Angeliki; Rossetti, Giacomo G.; Freudenmann, Alena; Iacovino, Luca G.; Dionellis, Vasilis S.; Sotiriou, Sotirios K.; Halazonetis, Thanos D.
• 署名单位: University of Geneva; Roche Holding
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4058
• DOI: 10.1038/s41586-024-07217-2
• 发表日期: 2024-04-11
• 页码: 433-+
• 关键词: poly(adp-ribose) polymerase; structural basis; dna-synthesis; timeless; repair; temozolomide; STABILITY; distinct; protein; genome

摘要

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 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.