DNA Repair and Global Sumoylation Are Regulated by Distinct Ubc9 Noncovalent Complexes
DNA Repair and Global Sumoylation Are Regulated by Distinct Ubc9 Noncovalent Complexes
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DOI：
10.1128/mcb.05188-11
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发表时间：
2011-06-01
影响因子：
5.3
通讯作者：
Boddy, Michael N.
中科院分区：
文献类型：
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作者：
Prudden, John;Perry, J. Jefferson P.;Boddy, Michael N.
全局SUMO化，SUMO链形成和基因组稳定都是由有限的酶库产生的输出。驱动这些过程的选择性的机制在很大程度上是未知的。在这里，通过晶体学分析，我们发现SUMO E2 Ubc9与Rad60 （SLD2）的SUMO样结构域形成非共价复合物。Ubc9: SLD2和Ubc9: SUMO非共价复合物在结构上是相似的，这表明SUMO或Rad60对Ubc9的差异招募为这种选择性提供了一种新的手段。事实上，通过破坏Ubc9: SLD2或Ubc9: SUMO非共价复合物来反卷积Ubc9的功能揭示了促进SUMO化的不同作用。Ubc9: SLD2在Nse2 SUMO E3连接酶依赖的DNA修复途径中起作用，而Ubc9: SUMO则通过Pli1 E3 SUMO连接酶促进全局SUMO化和链形成。此外，这种依赖pli1的SUMO链形成导致SUMO靶向泛素连接酶（STUbL）突变体的基因组不稳定表型。总的来说，我们确定，出乎意料的是，Ubc9非共价伴侣选择决定了sumoylation在不同细胞途径中的作用。
Global sumoylation, SUMO chain formation, and genome stabilization are all outputs generated by a limited repertoire of enzymes. Mechanisms driving selectivity for each of these processes are largely uncharacterized. Here, through crystallographic analyses we show that the SUMO E2 Ubc9 forms a noncovalent complex with a SUMO-like domain of Rad60 (SLD2). Ubc9: SLD2 and Ubc9: SUMO noncovalent complexes are structurally analogous, suggesting that differential recruitment of Ubc9 by SUMO or Rad60 provides a novel means for such selectivity. Indeed, deconvoluting Ubc9 function by disrupting either the Ubc9: SLD2 or Ubc9: SUMO noncovalent complex reveals distinct roles in facilitating sumoylation. Ubc9: SLD2 acts in the Nse2 SUMO E3 ligase-dependent pathway for DNA repair, whereas Ubc9: SUMO instead promotes global sumoylation and chain formation, via the Pli1 E3 SUMO ligase. Moreover, this Pli1-dependent SUMO chain formation causes the genome instability phenotypes of SUMO-targeted ubiquitin ligase (STUbL) mutants. Overall, we determine that, unexpectedly, Ubc9 noncovalent partner choice dictates the role of sumoylation in distinct cellular pathways.