Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks. We demonstrate that the ADP-ribose chromatin scars result in reduced endogenous levels of important chromatin modifications such as H3K9 acetylation, and that ARH3 patient cells exhibit measurable levels of deregulated transcription. Moreover, we show that the mono(ADP-ribose) scars are lost from the chromatin of ARH3-defective cells in the prolonged presence of PARP inhibition, and concomitantly that chromatin acetylation is restored to normal. Collectively, these data indicate that ARH3 can act as an eraser of ADP-ribose chromatin scars at sites of PARP activity during DNA single-strand break repair.

神经退行性变是具有 DNA 单链断裂修复遗传缺陷的个体的常见标志。受聚（ADP-核糖）代谢调节的过程。最近，从蛋白质中去除 ADP-核糖的 ARH3 (ADPRHL2)水解酶的突变与神经退行性疾病有关。在这里，我们发现ARH3突变的患者细胞在核心组蛋白上积累单（ADP-核糖）疤痕，这是最近修复的 DNA 单链断裂的分子记忆。我们证明，ADP-核糖染色质疤痕会导致重要染色质修饰（例如 H3K9 乙酰化）的内源水平降低，并且 ARH3 患者细胞表现出可测量水平的转录失调。此外，我们发现，在长时间存在 PARP 抑制的情况下，ARH3 缺陷细胞的染色质单（ADP-核糖）疤痕消失，同时染色质乙酰化恢复正常。总的来说，这些数据表明，在 DNA 单链断裂修复过程中，ARH3 可以充当 PARP 活性位点 ADP-核糖染色质疤痕的擦除器。