染色體雙股斷裂為DNA損傷中最嚴重的一種類型。酵母菌和哺乳類的Mre11-Rad50-Xrs2/Nbs1(MRX/N)-Sae2/Ctp1蛋白質複合體其的生理功能為移除DNA雙股斷裂端點上的二級結構、化學附加物、與DNA共價鍵結的拓撲異構酶或減數分裂專一性蛋白Spo11。MRX/N複合體也負責啟動「磷酸化檢查點」與「廣泛性小泛素蛋白質轉譯後修飾」兩個平行的DNA破損反應，協調DNA修補生化反應與細胞週期。然而，MRX/N複合體促進廣泛性小泛素蛋白質轉譯後修飾的反應機制還不是很清楚。本論文報導出芽酵母菌的Mre11蛋白質有兩個在演化上高度保留的小泛素交互作用結構區域 (SUMO-interacting motifs, SIMs)，Mre11SIM1 和 Mre11SIM2，可先後分別非共價性結合小泛素鍊或小泛素轉譯後修飾蛋白 (conjugated SUMO moieties, CSM)。Mre11SIM1在MRX複合體的組裝上扮演著重要角色；Mre11SIM2則能促進組裝完成的MRX複合體非共價性結合催化小泛素轉譯後修飾反應相關酵素，如E2/Ubc9與E3/Siz2，啟動廣泛性小泛素蛋白質轉譯後修飾反應，卻不影響磷酸化檢查點反應。我們也發現在減數分裂時，mre11SIM2突變株的性狀與mre11S、rad50S或sae2Δ等突變株一樣，大量累積由Spo11所催化的DNA雙股斷裂，卻無法進行核苷酸修剪作用，並將Spo11自DNA雙股斷裂點移除。本論文以MRX與DNA損傷修補機制為例，證明小泛素鍊或小泛素轉譯後修飾蛋白可利用非共價性蛋白質交互作用方式影響細胞蛋白質複合體的組裝與生理功能。

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 noncovalently facilitate the assembly and functions of multi-subunit protein complexes.

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