Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of DNA damage. Yet, PARPi function mainly by trapping PARP1 onto DNA with a wide range of potency among the clinically relevant inhibitors. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon at sites of DNA damage that correlates with PARPi k. Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA-binding protein recruitment. These results clarify how PARPi trap, shed new light on how PARPi function, and describe how PARPi properties correlate to trapping potency.

中文翻译：

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PARP 捕获受 PARP 抑制剂解离速率常数控制

聚（ADP-核糖）聚合酶 (PARP) 抑制剂 (PARPi) 是一类抗癌药物，可通过酶抑制 DNA 损伤位点的 PARP 活性。然而，PARPi 主要通过将 PARP1 捕获到 DNA 上来发挥作用，在临床相关抑制剂中具有广泛的效力。PARPi 如何捕获以及为什么有些捕获器是更好的捕获器仍然未知。在这里，我们表明捕获主要通过与 PARPi k 相关的 DNA 损伤位点的动力学现象发生。我们的结果表明，PARP 捕获并不是 PARP1 在 DNA 上的物理停滞，而是在没有其他 DNA 结合蛋白招募的情况下，PARP 重新结合受损 DNA 的可能性很高。这些结果阐明了 PARPi 如何捕获，为 PARPi 的功能提供了新的线索，并描述了 PARPi 特性如何与捕获效力相关。