一个保守的 SUMO 通路通过结合泛素介导的蛋白酶体降解来修复拓扑异构酶 DNA-蛋白质交联。
A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation.
机构信息
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Rockford, IL 61107, USA.
出版信息
Sci Adv. 2020 Nov 13;6(46). doi: 10.1126/sciadv.aba6290. Print 2020 Nov.
Topoisomerases form transient covalent DNA cleavage complexes to perform their reactions. Topoisomerase I cleavage complexes (TOP1ccs) are trapped by camptothecin and TOP2ccs by etoposide. Proteolysis of the trapped topoisomerase DNA-protein cross-links (TOP-DPCs) is a key step for some pathways to repair these lesions. We describe a pathway that features a prominent role of the small ubiquitin-like modifier (SUMO) modification for both TOP1- and TOP2-DPC repair. Both undergo rapid and sequential SUMO-2/3 and SUMO-1 modifications in human cells. The SUMO ligase PIAS4 is required for these modifications. RNF4, a SUMO-targeted ubiquitin ligase (STUbL), then ubiquitylates the TOP-DPCs for their subsequent degradation by the proteasome. This pathway is conserved in yeast with Siz1 and Slx5-Slx8, the orthologs of human PIAS4 and RNF4.
拓扑异构酶形成瞬时的共价 DNA 断裂复合物以执行其反应。拓扑异构酶 I 断裂复合物 (TOP1ccs) 被喜树碱捕获，拓扑异构酶 II 断裂复合物 (TOP2ccs) 被依托泊苷捕获。捕获的拓扑异构酶 DNA-蛋白交联 (TOP-DPCs) 的蛋白水解是修复这些损伤的一些途径的关键步骤。我们描述了一条途径，其特征是小泛素样修饰物 (SUMO) 修饰在 TOP1 和 TOP2-DPC 修复中都具有突出作用。在人类细胞中，两者都经历快速和顺序的 SUMO-2/3 和 SUMO-1 修饰。PIAS4 是这些修饰所必需的 SUMO 连接酶。然后，SUMO 靶向泛素连接酶 (STUbL) RNF4 使 TOP-DPCs 泛素化，随后通过蛋白酶体进行降解。这个途径在酵母中是保守的，酵母中的 Siz1 和 Slx5-Slx8 是人类 PIAS4 和 RNF4 的同源物。
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