PARP1特异性抑制剂显示PARP1去捕获活性
PARP1-specific inhibitor displays PARP1-detrapping activity.
摘要(中文译文)
针对主要同源重组缺陷型肿瘤，PARP抑制剂的成功应用依赖于其抑制PARP1和PARP2催化活性的能力，导致二者滞留于DNA损伤位点，即所谓的PARP“捕获”。不同的PARP抑制剂在捕获能力上存在差异，因而其所致毒性也不同。在此，我们构建了一种可诱导的互补系统，用于表达带标签的PARP1变体，以评估PARP1催化位点不同突变对ADP-核糖基化（ADPr）活性、捕获及细胞存活的影响。通过检测这些细胞系对不同PARP抑制剂的行为和敏感性，我们发现saruparib——一种首创的PARP1特异性抑制剂——可促进某些PARP1催化突变体的释放，并导致对该抑制剂的耐药。我们还鉴定了一种PARP1催化突变体，其单（ADP-核糖基）化活性完整但缺乏多（ADP-核糖基）化，由此我们得以证明单（ADP-核糖基）化对PARP1从DNA损伤位点释放具有重要贡献。
Abstract
The successful use of PARP inhibitors against primarily homologous recombination-deficient tumors relies on their ability to inhibit the catalytic activity of PARP1 and PARP2, leading to their retention at sites of DNA damage, known as PARP "trapping." Different PARP inhibitors vary in their trapping ability and thus in their resulting toxicity. Here, we develop an inducible complementation system for the expression of tagged PARP1 variants to assess the impact of different mutations in the PARP1 catalytic site on ADP-ribosylation (ADPr) activity, trapping, and cell survival. Testing these cell lines for their behavior and sensitivity to different PARP inhibitors, we find that saruparib, a first-in-class PARP1-specific inhibitor, promotes the release of certain PARP1 catalytic mutants and resistance to this inhibitor. We also characterize a PARP1 catalytic mutant with intact mono(ADP-ribosyl)ation activity but devoid of poly(ADP-ribosyl)ation, enabling us to demonstrate a significant contribution of mono(ADP-ribosyl)ation toward PARP1 release from sites of DNA damage.
如何引用
AMA
Kira Schützenhofer, Ellen Laker, Kyle Tsang, Domagoj Baretić, Marcin J Suskiewicz, Florian F H Zobel, et al. PARP1-specific inhibitor displays PARP1-detrapping activity.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117350.
APA
Kira Schützenhofer, Ellen Laker, Kyle Tsang, Domagoj Baretić, Marcin J Suskiewicz, Florian F H Zobel, et al (2026). PARP1-specific inhibitor displays PARP1-detrapping activity.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117350
GB/T 7714
Kira Schützenhofer, Ellen Laker, Kyle Tsang, Domagoj Baretić, Marcin J Suskiewicz, Florian F H Zobel, et al. PARP1-specific inhibitor displays PARP1-detrapping activity.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117350.
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