S. cerevisiae Mre11 recruits conjugated SUMO moieties to facilitate the assembly and function of the Mre11-Rad50-Xrs2 complex.
S. cerevisiae Mre11 recruits conjugated SUMO moieties to facilitate the assembly and function of the Mre11-Rad50-Xrs2 complex.
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DOI：
10.1093/nar/gkv1523
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发表时间：
2016-03-18
影响因子：
14.9
通讯作者：
Wang TF
中科院分区：
文献类型：
--
作者：
Chen YJ;Chuang YC;Chuang CN;Cheng YH;Chang CR;Leng CH;Wang TF
染色体双链断裂（DSB）是最具挑战性的DNA损伤类型。酵母和哺乳动物Mre 11-Rad 50-Xrs 2/Nbs 1（MRX/N）-Sae 2/Ctp 1复合物催化二级结构、化学加合物或共价连接蛋白诱导的DSB切除。MRX/N还启动两个平行的DNA损伤反应-检查点磷酸化和全局SUMO化-以增强细胞修复DSB的能力。然而，这种SUMO介导的反应的分子机制尚不完全清楚。在这项研究中，我们报告说，酿酒酵母Mre 11可以非共价募集共轭SUMO部分，特别是聚SUMO链。Mre 11有两个进化上保守的SUMO相互作用基序，Mre 11 SIM 1和Mre 11 SIM 2，它们位于Mre 11的最外表面。Mre 11 SIM 1是MRX组装不可或缺的。Mre 11 SIM 2将MRX与SUMO酶（E2/Ubc 9和E3/Siz 2）非共价连接，以促进DNA修复蛋白的整体SUMO化。Mre 11 SIM 2的作用独立于检查点磷酸化。在减数分裂期间，mre 11 SIM 2突变体（如mre 11 S、rad 50 S和sae 2 Δ）允许Spo 11诱导的DSB的启动，但不能加工。使用MRX和DSB修复作为模型，我们的工作揭示了一个一般的原则，其中共轭SUMO部分非共价促进多亚基蛋白质复合物的组装和功能。
Double-strand breaks (DSBs) in chromosomes are the most challenging type of DNA damage. The yeast and mammalian Mre11-Rad50-Xrs2/Nbs1 (MRX/N)-Sae2/Ctp1 complex catalyzes the resection of DSBs induced by secondary structures, chemical adducts or covalently-attached proteins. MRX/N also initiates two parallel DNA damage responses—checkpoint phosphorylation and global SUMOylation—to boost a cell's ability to repair DSBs. However, the molecular mechanism of this SUMO-mediated response is not completely known. In this study, we report that Saccharomyces cerevisiae Mre11 can non-covalently recruit the conjugated SUMO moieties, particularly the poly-SUMO chain. Mre11 has two evolutionarily-conserved SUMO-interacting motifs, Mre11SIM1 and Mre11SIM2, which reside on the outermost surface of Mre11. Mre11SIM1 is indispensable for MRX assembly. Mre11SIM2 non-covalently links MRX with the SUMO enzymes (E2/Ubc9 and E3/Siz2) to promote global SUMOylation of DNA repair proteins. Mre11SIM2 acts independently of checkpoint phosphorylation. During meiosis, the mre11SIM2 mutant, as for mre11S, rad50S and sae2Δ, allows initiation but not processing of Spo11-induced DSBs. Using MRX and DSB repair as a model, our work reveals a general principle in which the conjugated SUMO moieties non-covalently facilitate the assembly and functions of multi-subunit protein complexes.