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^1,2,3,4,5,6. 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.

癌症治疗的一个重要进展是聚（ADP-核糖）聚合酶（PARP）抑制剂的开发，用于治疗同源重组（HR）缺陷的癌症^1,2,3,4,5,6。 PARP 抑制剂将 PARP 捕获在 DNA 上。被捕获的 PARP 被认为会阻止复制体的进展，导致 DNA 双链断裂的形成，需要 HR 进行修复⁷。在这里，我们展示了 PARP1 与 TIMELESS 和 TIPIN 一起发挥作用，保护早期 S 期的复制体免受转录-复制冲突。此外，HR缺陷的PARP抑制剂的合成致死性是由于无法修复由转录-复制冲突引起的DNA损伤，而不是由于被捕获的PARP。沿着这些思路，抑制早期S期的转录延伸使HR缺陷细胞对PARP抑制剂产生抗性，并且通过小干扰RNA耗尽PARP1对于HR缺陷来说是合成致死的。因此，抑制 PARP1 酶活性可能足以在 HR 缺乏的情况下提高治疗效果。