小柯机器人

瑞士日内瓦大学Thanos D. Halazonetis研究小组发现，转录-复制冲突是PARP抑制剂敏感性的基础。相关论文于2024年3月20日在线发表在《自然》杂志上。

研究人员表示，癌症治疗领域的一项重要进展是开发出了多聚（ADP-核糖）聚合酶（PARP）抑制剂，用于治疗同源重组（HR）缺陷癌症。PARP抑制剂可捕获DNA上的PARP。被困的PARP被认为会阻碍复制体的进展，导致DNA双链断裂的形成，而这种断裂需要HR来修复。

研究人员发现，PARP1与TIMELESS和TIPIN共同发挥作用，保护S期早期的复制体不受转录-复制冲突的影响。此外，缺乏HR的PARP抑制剂的合成致死性是由于无法修复转录-复制冲突造成的DNA损伤，而不是由于PARP被困。根据这些思路，抑制S期早期的转录延伸会使HR缺陷细胞对PARP抑制剂产生抗性，而通过小干扰RNA耗尽PARP1会对HR缺陷细胞产生合成致死作用。因此，抑制PARP1酶的活性可能足以在HR缺陷的情况下达到治疗效果。

附：英文原文

Title: Transcription–replication conflicts underlie sensitivity to PARP inhibitors

Author: Petropoulos, Michalis, Karamichali, Angeliki, Rossetti, Giacomo G., Freudenmann, Alena, Iacovino, Luca G., Dionellis, Vasilis S., Sotiriou, Sotirios K., Halazonetis, Thanos D.

Issue&Volume: 2024-03-20

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 cancers1,2,3,4,5,6. 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.

DOI: 10.1038/s41586-024-07217-2

Source: https://www.nature.com/articles/s41586-024-07217-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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