HPF1 在调节 PARP1 和 PARP2 活性方面的双重功能。

Dual function of HPF1 in the modulation of PARP1 and PARP2 activities.

机构信息

Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk, Russia.

Novosibirsk State University, Novosibirsk, Russia.

出版信息

Commun Biol. 2021 Nov 3;4(1):1259. doi: 10.1038/s42003-021-02780-0.

Poly(ADP-ribosyl)ation catalyzed by poly(ADP-ribose) polymerases (PARPs) is one of the immediate cellular responses to DNA damage. The histone PARylation factor 1 (HPF1) discovered recently to form a joint active site with PARP1 and PARP2 was shown to limit the PARylation activity of PARPs and stimulate their NAD-hydrolase activity. Here we demonstrate that HPF1 can stimulate the DNA-dependent and DNA-independent autoPARylation of PARP1 and PARP2 as well as the heteroPARylation of histones in the complex with nucleosome. The stimulatory action is detected in a defined range of HPF1 and NAD concentrations at which no HPF1-dependent enhancement in the hydrolytic NAD consumption occurs. PARP2, comparing with PARP1, is more efficiently stimulated by HPF1 in the autoPARylation reaction and is more active in the heteroPARylation of histones than in the automodification, suggesting a specific role of PARP2 in the ADP-ribosylation-dependent modulation of chromatin structure. Possible role of the dual function of HPF1 in the maintaining PARP activity is discussed.

聚（ADP-核糖）聚合酶（PARPs）催化的聚（ADP-核糖）化是细胞对 DNA 损伤的即刻反应之一。最近发现组蛋白 PAR 化因子 1（HPF1）与 PARP1 和 PARP2 形成联合活性位点，限制 PARPs 的 PAR 化活性并刺激其 NAD 水解酶活性。本文证明 HPF1 可刺激 PARP1 和 PARP2 的 DNA 依赖性和 DNA 非依赖性自 PAR 化以及核小体复合物中组蛋白的异 PAR 化。在 HPF1 和 NAD 浓度的特定范围内检测到刺激作用，在此范围内不会发生依赖于 HPF1 的水解 NAD 消耗的增强。与 PARP1 相比，PARP2 在自 PAR 化反应中被 HPF1 更有效地刺激，并且在组蛋白的异 PAR 化中比自动修饰更活跃，这表明 PARP2 在 ADP-核糖基化依赖的染色质结构调节中具有特定作用。讨论了 HPF1 的双重功能在维持 PARP 活性中的可能作用。