Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences (ICBFM SB RAS), Novosibirsk, Russia.
Commun Biol. 2024 Sep 15;7(1):1148. doi: 10.1038/s42003-024-06811-4.
The formation of nuclear biomolecular condensates is often associated with local accumulation of proteins at a site of DNA damage. The key role in the formation of DNA repair foci belongs to PARP1, which is a sensor of DNA damage and catalyzes the synthesis of poly(ADP-ribose) attracting repair factors. We show here that biogenic cations such as Mg, Ca, Mn, spermidine, or spermine can induce liquid-like assembly of poly(ADP-ribosyl)ated [PARylated] PARP1 into multimolecular associates (hereafter: self-assembly). The self-assembly of PARylated PARP1 affects the level of its automodification and hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG). Furthermore, association of PARylated PARP1 with repair proteins strongly stimulates strand displacement DNA synthesis by DNA polymerase β (Pol β) but has no noticeable effect on DNA ligase III activity. Thus, liquid-like self-assembly of PARylated PARP1 may play a critical part in the regulation of i) its own activity, ii) PARG-dependent hydrolysis of poly(ADP-ribose), and iii) Pol β-mediated DNA synthesis. The latter can be considered an additional factor influencing the choice between long-patch and short-patch DNA synthesis during repair.
核生物分子凝聚物的形成通常与蛋白质在 DNA 损伤部位的局部积累有关。PARP1 在 DNA 修复焦点的形成中起着关键作用，它是 DNA 损伤的传感器，并催化多聚（ADP-核糖）的合成，吸引修复因子。我们在这里表明，生物源阳离子，如 Mg、Ca、Mn、精胺或亚精胺，可以诱导聚（ADP-核糖基）化的 PARP1 聚集体（以下简称：自组装）形成液态多分子复合物。PARP1 的 PAR 化自组装影响其自动修饰水平和聚（ADP-核糖）水解酶（PARG）对多聚（ADP-核糖）的水解。此外，PARP1 与修复蛋白的缔合强烈刺激 DNA 聚合酶 β（Pol β）的链置换 DNA 合成，但对 DNA 连接酶 III 活性没有明显影响。因此，PARP1 的液态自组装可能在以下几个方面发挥关键作用：i）其自身活性的调节，ii）PARG 依赖性多聚（ADP-核糖）的水解，以及 iii）Pol β 介导的 DNA 合成。后一种情况可以被认为是在修复过程中影响长补丁和短补丁 DNA 合成之间选择的另一个因素。
