Maria V. Sukhanova, Rashid O. Anarbaev, Ekaterina A. Maltseva, Mikhail M. Kutuzov, Olga I. Lavrik
{"title":"Divalent and multivalent cations control liquid-like assembly of poly(ADP-ribosyl)ated PARP1 into multimolecular associates in vitro","authors":"Maria V. Sukhanova, Rashid O. Anarbaev, Ekaterina A. Maltseva, Mikhail M. Kutuzov, Olga I. Lavrik","doi":"10.1038/s42003-024-06811-4","DOIUrl":null,"url":null,"abstract":"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 Mg2+, Ca2+, Mn2+, spermidine3+, or spermine4+ 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. Formation of biomolecular condensate via liquid-like assembly of PARylated PARP1 is driven by biogenic cations. This assembly regulates autoPARylation of PARP1, PARG-dependent hydrolysis of poly(ADP-ribose) and Polβ-mediated DNA synthesis.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06811-4.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Communications Biology","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s42003-024-06811-4","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 Mg2+, Ca2+, Mn2+, spermidine3+, or spermine4+ 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. Formation of biomolecular condensate via liquid-like assembly of PARylated PARP1 is driven by biogenic cations. This assembly regulates autoPARylation of PARP1, PARG-dependent hydrolysis of poly(ADP-ribose) and Polβ-mediated DNA synthesis.
核生物分子凝聚体的形成往往与 DNA 损伤部位蛋白质的局部聚集有关。在 DNA 修复灶形成过程中起关键作用的是 PARP1,它是 DNA 损伤的传感器,能催化聚(ADP-核糖)吸引修复因子的合成。我们在此表明,Mg2+、Ca2+、Mn2+、精胺3+或精胺4+等生物阳离子可诱导聚(ADP-核糖基)[PARylated] PARP1液态组装成多分子联合体(以下简称:自组装)。PARylated PARP1 的自组装会影响其自动调节和聚(ADP-核糖)糖水解酶(PARG)水解聚(ADP-核糖)的水平。此外,PARylated PARP1 与修复蛋白的结合会强烈刺激 DNA 聚合酶 β(Pol β)的链置换 DNA 合成,但对 DNA 连接酶 III 的活性没有明显影响。因此,PARylated PARP1 的液态自组装可能在以下调节过程中起着关键作用:i)自身活性;ii)PARG 依赖性水解聚(ADP-核糖);iii)Pol β 介导的 DNA 合成。后者可被视为影响修复过程中长补丁和短补丁 DNA 合成之间选择的另一个因素。在生物阳离子的驱动下,PAR 化的 PARP1 通过液态组装形成生物分子凝聚物。这种组装调节 PARP1 的自身 PARylation 、PARG 依赖性的聚(ADP-核糖)水解和 Polβ 介导的 DNA 合成。
期刊介绍:
Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.