Department of Biochemistry, University of Colorado Boulder, Boulder, CO, 80309, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
Nat Commun. 2021 Feb 2;12(1):736. doi: 10.1038/s41467-021-20998-8.
Poly-(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) are key enzymes in the DNA damage response. Four different inhibitors (PARPi) are currently in the clinic for treatment of ovarian and breast cancer. Recently, histone PARylation Factor 1 (HPF1) has been shown to play an essential role in the PARP1- and PARP2-dependent poly-(ADP-ribosylation) (PARylation) of histones, by forming a complex with both enzymes and altering their catalytic properties. Given the proximity of HPF1 to the inhibitor binding site both PARPs, we hypothesized that HPF1 may modulate the affinity of inhibitors toward PARP1 and/or PARP2. Here we demonstrate that HPF1 significantly increases the affinity for a PARP1 - DNA complex of some PARPi (i.e., olaparib), but not others (i.e., veliparib). This effect of HPF1 on the binding affinity of Olaparib also holds true for the more physiologically relevant PARP1 - nucleosome complex but does not extend to PARP2. Our results have important implications for the interpretation of PARP inhibition by current PARPi as well as for the design and analysis of the next generation of clinically relevant PARP inhibitors.
聚（ADP-核糖）聚合酶 1 和 2（PARP1 和 PARP2）是 DNA 损伤反应中的关键酶。目前有四种不同的抑制剂（PARPi）用于治疗卵巢癌和乳腺癌。最近，组蛋白 PAR 化因子 1（HPF1）已被证明在 PARP1 和 PARP2 依赖性组蛋白聚（ADP-核糖）（PARylation）中发挥重要作用，其通过与两种酶形成复合物并改变其催化特性。鉴于 HPF1 与抑制剂结合位点的 PARP1 和 PARP2 都很接近，我们假设 HPF1 可能调节抑制剂对 PARP1 和/或 PARP2 的亲和力。在这里，我们证明 HPF1 显著增加了一些 PARPi（即奥拉帕尼）与 PARP1-DNA 复合物的亲和力，但不是其他 PARPi（即 veliparib）。HPF1 对奥拉帕尼结合亲和力的这种影响也适用于更具生理相关性的 PARP1-核小体复合物，但不适用于 PARP2。我们的研究结果对当前 PARPi 对 PARP 抑制的解释以及下一代临床相关 PARP 抑制剂的设计和分析具有重要意义。
