SUMO wrestles breaks to the nuclear ring's edge
SUMO wrestles breaks to the nuclear ring's edge
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相扑摔跤突破核环边缘
DOI：
10.1080/15384101.2016.1216904
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发表时间：
2016
期刊：
影响因子：
4.3
通讯作者：
S. Gasser
中科院分区：
文献类型：
--
作者：
Chihiro Horigome;S. Gasser
DNA双链断裂（DSB）的准确修复对于细胞存活和维持基因组完整性至关重要。在大多数情况下，细胞通过采用2种高度保守的修复途径来抵消DSB：非同源末端连接（NHEJ）和同源重组（HR）。当这些途径由于缺乏同源供体序列或阻断端对端连接的条件而受损时，发生替代修复，例如断裂诱导复制（BIR）或不精确或微同源介导的末端连接。由于这些替代途径往往具有高度致突变性，因此修复途径的选择至少在3个水平上受到控制：细胞周期阶段、损伤的染色质背景和断裂的亚核位置。在芽殖酵母中，持久性DSB被募集到核外围，并通过Nup 84亚复合物与核孔或与称为Mps 3的内膜SUN结构域蛋白相关联。细胞周期阶段影响靶位点的选择：孔用于细胞周期的G1和S/G2期，而Mps 3结合仅发生在S/G2期细胞中。在S期细胞中，在延长的三重重复序列处的崩溃或停滞的复制叉以及被侵蚀的端粒被证明转移到核孔中。重要的是，这2个核周结合位点差异影响修复结果。Mps 3似乎隔离切除的DSB，从而抑制异常重组事件，而核孔涉及非经典修复途径，如BIR和不精确的末端连接（参见综述和Horigome等人）。然而，在这些位点之间存在一些串扰，因为Mps 3可能有助于适当的孔组装，使得基于mps 3突变体的修复数据的解释复杂化。最近的几篇论文强调了SUMO（小泛素样修饰物）作为DSB核周锚定驱动剂的重要性。核孔含有SUMO蛋白酶Ulp 1和Slx 5/Slx 8 SUMO靶向泛素连接酶（STUbL），早期的遗传研究表明，核孔、Slx 5/Slx 8和蛋白酶体在DNA修复中作用于相同的途径。广泛的SUMO化事件在多个物种中响应DNA断裂而发生，使得参与各种修复途径的因子被修饰。有趣的是，Horigome等人表明，DSB在核膜上的重新定位的靶点取决于E3连接酶Siz 2和Mms 21介导的SUMO化的性质。在G1期和S期细胞中，Mms 21和Siz 2协同沉积的聚SUMO化链招募Slx 5/Slx 8 STUbL持续断裂。然后Slx 5介导与核孔亚复合物Nup 84的结合。当Slx 5通过DNA结合结构域靶向标记的基因座时，即使在没有损伤的情况下，Slx 5也可以单独将DNA转移到孔中。Slx 5的这种人工靶向绕过了重新定位对聚SUMO化的需要。尽管如此，在内源性断裂和缩短的端粒中，SUMO化和Slx 8都需要稳定Slx 5结合并允许受损位点转移到Nup 84。在S期细胞中，由SMC 5/6-Mms 21 E3复合物介导的单SUMO化与切除的DSB与SUN结构域蛋白Mps 3的关联相关，并且这可以在不存在Slx 5的情况下发生。此外，SUMO残基（4个首尾相连的Smt 3残基）的聚合物与未受损的染色质基因座的靶向结合允许其与孔结合，而单个Smt 3残基（单SUMO）的靶向将相同的基因座转移到Mps 3。重要的是，polySUMO依赖性的重新定位到孔仍然需要Slx 5，认为这种STUbL及其SUMO相互作用基序必须识别polySUMO链来介导重新定位（图1）。问题是一个或多个SUMO化靶点对于重新定位是否至关重要。这可能取决于损坏的类型。在侵蚀端粒RPA被证明是SUMO化的目标。由于它招募Slx 5/Slx 8，因此提出参与将端粒靶向到核孔以用于替代修复途径。在果蝇中，Ryu等人发现异染色质中的DSB从紧密的染色质结构域转移，并以SUMO化和STUbL（Dgrn）依赖性方式与核孔（Nup 107或Nup 160）和/或SUN结构域蛋白（Koi或Spag 4）结合。在酵母中，核孔和SUN结构域蛋白与Smc 5/6及其靶向SUMO连接酶Mms 21（Nse 2）协同工作，但2个核周结合位点相互独立地起作用。果蝇Slx 5/Slx 8同源物（Dgrn）的募集需要SUMO连接酶Nse 2和dPIAS，其修饰
The accurate repair of DNA double-strand breaks (DSBs) is essential for cell survival and maintenance of genome integrity. In most cases, cells counteract DSBs by employing 2 highly conserved repair pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). When these pathways are impaired due to a lack of homologous donor sequence or conditions that block end-to-end ligation, alternative repair occurs, such as break-induced replication (BIR) or else imprecise or microhomology-mediated end-joining. Since these alternative pathways tend to be highly mutagenic, the choice of the repair pathway is controlled on at least 3 levels: by cell cycle stage, the chromatin context of the damage and the subnuclear position of the breaks. In budding yeast, persistent DSBs are recruited to the nuclear periphery and associate with nuclear pores through the Nup84 subcomplex or with an inner nuclear membrane SUN domain protein called Mps3. The cell cycle stage influences target site choice: pores are used in both G1 and S/G2-phases of cell cycle, while Mps3 binding only occurs in S/G2-phase cells. In S-phase cells, collapsed or stalled replication forks at extended triplet repeats, as well as eroded telomeres, were shown to shift to nuclear pores. Importantly, these 2 perinuclear binding sites differentially affected the repair outcome. Mps3 appears to sequester resected DSBs and thereby inhibits aberrant recombination events, whereas nuclear pores are implicated in the non-canonical repair pathways such as BIR and imprecise end-joining (see reviews and Horigome et al). There is, however, some cross-talk between the sites, as Mps3 may contribute to proper pore assembly, complicating the interpretation of repair data based on mps3 mutants. Several recent papers highlight the importance of SUMO (small ubiquitin-like modifier) as a driver for perinuclear anchoring of DSBs. The nuclear pore harbors the SUMO protease Ulp1 and Slx5/Slx8 SUMO-targeted ubiquitin ligase (STUbL) and an earlier genetic study revealed that nuclear pores, Slx5/Slx8, and the proteasome act on the same pathway in DNA repair. Extensive SUMOylation events occur in response to DNA breaks in multiple species, such that factors involved in various pathways of repair become modified. Intriguingly, Horigome et al showed that the target of DSB relocation at the nuclear envelope depends on the nature of SUMOylation mediated by the E3 ligases Siz2 and Mms21. In G1and S-phase cells, a polySUMOylation chain deposited coordinately by Mms21 and Siz2 recruits the Slx5/Slx8 STUbL to persistent breaks. Then Slx5 mediates binding to the nuclear pore subcomplex, Nup84. Slx5 alone can shift DNA to pores when it is targeted to a tagged locus through a DNA binding domain, even in the absence of damage. This artificial targeting of Slx5 bypasses the need for polySUMOylation for relocation. Nonetheless, at endogenous breaks and shortened telomeres, both SUMOylation and Slx8 are needed to stabilize Slx5 binding and allow the damaged site to shift to the Nup84. In S-phase cells, monoSUMOylation mediated by the SMC5/6-Mms21 E3 complex correlated with the association of resected DSBs with the SUN domain protein, Mps3, and this can occur in the absence of Slx5. Moreover, the targeted binding of a polymer of SUMO residues (4 head-to-tail linked Smt3 residues) to an undamaged chromatin locus, allowed it to bind to pores, while the targeting of a single Smt3 residue (mono-SUMO), shifted the same locus to Mps3. Importantly, the polySUMO-dependent relocation to pores still required Slx5, arguing that this STUbL and its SUMO interacting motifs must recognize a polySUMO chain to mediate relocation (Fig. 1). The question arises as to whether one or multiple SUMOylation targets are crucial for the relocation. This may well depend on the type of damage. At eroded telomeres RPA was shown to be a SUMOylation target. Since it recruits Slx5/Slx8, it was proposed to be involved in targeting the telomere to nuclear pores for an alternative pathway of repair. In Drosophila, Ryu et al. showed that DSBs in heterochromatin shift away from the compacted chromatin domain and bind to either the nuclear pore (Nup107 or Nup160) and/or the SUN domain proteins (Koi or Spag4) in a SUMOylationand STUbL (Dgrn)-dependent manner. As in yeast, both nuclear pores and the SUN domain proteins work in concert with Smc5/6 and its targeted SUMO ligase Mms21 (Nse2), yet the 2 perinuclear binding sites act independently from each other. The recruitment of the fly Slx5/Slx8 homolog (Dgrn) requires SUMO ligases Nse2 and dPIAS, which modifies