Department of Cell and Molecular Biology, Karolinska Institutet, Biomedicum, Solnavägen 9, 17165 Stockholm, Sweden.
Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
J Cell Sci. 2021 Feb 8;134(3):jcs247809. doi: 10.1242/jcs.247809.
DNA damage-induced SUMOylation serves as a signal for two antagonizing proteins that both stimulate repair of DNA double-strand breaks (DSBs). Here, we demonstrate that the SUMO-dependent recruitment of the deubiquitylating enzyme ataxin-3 to DSBs, unlike recruitment of the ubiquitin ligase RNF4, additionally depends on poly [ADP-ribose] polymerase 1 (PARP1)-mediated poly(ADP-ribosyl)ation (PARylation). The co-dependence of ataxin-3 recruitment on PARylation and SUMOylation temporally confines ataxin-3 to DSBs immediately after occurrence of DNA damage. We propose that this mechanism ensures that ataxin-3 prevents the premature removal of DNA repair proteins only during the early phase of the DSB response and does not interfere with the subsequent timely displacement of DNA repair proteins by RNF4. Thus, our data show that PARylation differentially regulates SUMO-dependent recruitment of ataxin-3 and RNF4 to DSBs, explaining how both proteins can play a stimulatory role at DSBs despite their opposing activities.
DNA 损伤诱导的 SUMO 化可作为两种拮抗蛋白的信号，这两种蛋白均能刺激 DNA 双链断裂 (DSB) 的修复。在这里，我们证明与招募泛素连接酶 RNF4 不同，DNA 双链断裂处 SUMO 依赖性募集去泛素化酶 ataxin-3 还依赖于聚 [ADP-核糖] 聚合酶 1 (PARP1) 介导的聚 ADP-核糖化 (PARylation)。ataxin-3 的募集与 PARylation 和 SUMOylation 的共同依赖性在 DNA 损伤发生后立即将 ataxin-3 暂时限制在 DSB 处。我们提出，该机制确保 ataxin-3 仅在 DSB 反应的早期阶段防止 DNA 修复蛋白过早去除，并且不干扰随后由 RNF4 对 DNA 修复蛋白的及时置换。因此，我们的数据表明 PARylation 差异调节 ataxin-3 和 RNF4 向 DSB 的 SUMO 依赖性募集，解释了尽管这两种蛋白的活性相反，但它们如何均能在 DSB 处发挥刺激作用。
