Esc2 orchestrates substrate-specific sumoylation by acting as a SUMO E2 cofactor in genome maintenance.
Esc2 orchestrates substrate-specific sumoylation by acting as a SUMO E2 cofactor in genome maintenance.
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DOI：
10.1101/gad.344739.120
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发表时间：
2021-02-01
影响因子：
10.5
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Li S;Bonner JN;Wan B;So S;Mutchler A;Gonzalez L;Xue X;Zhao X
在这项研究中，Li等人着手研究芽殖酵母中保守的基因组稳定性因子Esc 2及其在DNA损伤诱导的sumo化中的作用。使用体外和体内方法，作者提出Esc 2在不同的DNA结构中作为SUMO E2辅因子，以促进特定底物的SUMO化和基因组的维持。SUMO修饰通过靶向数百种蛋白质来调节不同的细胞过程。然而，有限数量的类小泛素化酶提出了如何有效地修饰如此大量的底物的问题。具体而言，基因组维持因子如何在DNA复制和修复位点动态地SUMO化以调节其功能还知之甚少。在这里，我们证明了保守的酵母Esc2蛋白在这一过程中作为SUMO E2辅因子的作用。Esc2是基因组稳定性所必需的，并与霍利迪连接和复制叉结构结合。我们的靶向筛选发现Esc 2促进霍利迪连接溶解复合物和特定复制体蛋白的类小泛素化。Esc 2不通过与底物或其共同的SUMO E3的稳定相互作用引起这些效应。相反，我们表明，SUMO样结构域的ESC2刺激SUMO化利用非共价SUMO结合位点的E2酶。Esc 2在类小泛素化中的作用是Holliday连接清除和基因组稳定性所必需的。因此，我们的研究结果表明，Esc2作为SUMO E2辅因子在不同的DNA结构，以促进特定底物的SUMO化和基因组的维护。
In this study, Li et al. set out to investigate the conserved genome stability factor Esc2 in budding yeast and its roles in DNA damage-induced sumoylation. Using in vitro and in vivo approaches, the authors propose that Esc2 acts as a SUMO E2 cofactor at distinct DNA structures to promote the sumoylation of specific substrates and genome maintenance. SUMO modification regulates diverse cellular processes by targeting hundreds of proteins. However, the limited number of sumoylation enzymes raises the question of how such a large number of substrates are efficiently modified. Specifically, how genome maintenance factors are dynamically sumoylated at DNA replication and repair sites to modulate their functions is poorly understood. Here, we demonstrate a role for the conserved yeast Esc2 protein in this process by acting as a SUMO E2 cofactor. Esc2 is required for genome stability and binds to Holliday junctions and replication fork structures. Our targeted screen found that Esc2 promotes the sumoylation of a Holliday junction dissolution complex and specific replisome proteins. Esc2 does not elicit these effects via stable interactions with substrates or their common SUMO E3. Rather, we show that a SUMO-like domain of Esc2 stimulates sumoylation by exploiting a noncovalent SUMO binding site on the E2 enzyme. This role of Esc2 in sumoylation is required for Holliday junction clearance and genome stability. Our findings thus suggest that Esc2 acts as a SUMO E2 cofactor at distinct DNA structures to promote the sumoylation of specific substrates and genome maintenance.
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