Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance.
Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance.
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DOI：
10.1016/j.molcel.2015.10.023
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发表时间：
2015-12-17
期刊：
影响因子：
16
通讯作者：
Branzei D
中科院分区：
文献类型：
--
作者：
Menolfi D;Delamarre A;Lengronne A;Pasero P;Branzei D
保守的Smc 5/6复合物的基本功能仍然难以捉摸。为了揭示其在基因组维持中的作用，我们建立了酿酒酵母细胞周期调节等位基因，使Smc 5/6组分限制为S或G2/M。Smc 5/6的基本功能完全选择性地分离到G2/M期。基因筛选，成为可能与产生的等位基因确定的过程中，至关重要的依赖于Smc 5/6，特别是在G2/M：代谢的DNA重组结构引发的内源性复制应力，并通过位于复制后期区域的自然暂停位点复制。在第一个过程中，Smc 5/6调节重组中间体的重塑，与溶解活性合作。在第二，Smc 5/6防止染色体脆性和毒性重组煽动长时间暂停和叉保护复合物，Tof 1-Csm 3。因此，我们的研究结果剖析了Smc 5/6的基本作用，并揭示了DNA损伤耐受性和暂停位点复制的组合缺陷会导致重组介导的DNA损伤，我们建议驱动发育和癌症易感性疾病。细胞周期调控的等位基因揭示Smc 5/6在G2/M期分离的基本功能用新的亚型等位基因进行遗传筛选鉴定依赖于Smc 5/6的过程Smc 5/6作用于内源性复制应激触发的重组结构Smc 5/6通过自然暂停位点防止脆性并介导复制Menolfi et al.探讨Smc 5/6复合物在增殖中的作用。细胞周期调控等位基因揭示Smc 5/6在G2/M期分离的基本功能。与产生的等位基因的遗传筛选支持Smc 5/6在内源性复制应激引发的重组结构的代谢中的作用，以及通过自然暂停位点的复制。
The essential functions of the conserved Smc5/6 complex remain elusive. To uncover its roles in genome maintenance, we established Saccharomyces cerevisiae cell-cycle-regulated alleles that enable restriction of Smc5/6 components to S or G2/M. Unexpectedly, the essential functions of Smc5/6 segregated fully and selectively to G2/M. Genetic screens that became possible with generated alleles identified processes that crucially rely on Smc5/6 specifically in G2/M: metabolism of DNA recombination structures triggered by endogenous replication stress, and replication through natural pausing sites located in late-replicating regions. In the first process, Smc5/6 modulates remodeling of recombination intermediates, cooperating with dissolution activities. In the second, Smc5/6 prevents chromosome fragility and toxic recombination instigated by prolonged pausing and the fork protection complex, Tof1-Csm3. Our results thus dissect Smc5/6 essential roles and reveal that combined defects in DNA damage tolerance and pausing site-replication cause recombination-mediated DNA lesions, which we propose to drive developmental and cancer-prone disorders. Cell-cycle-regulated alleles reveal Smc5/6-essential functions to segregate in G2/M Genetic screen with new hypomorphic allele identifies processes relying on Smc5/6 Smc5/6 acts on recombination structures triggered by endogenous replication stress Smc5/6 prevents fragility and mediates replication through natural pausing sites Menolfi et al. explore the roles of the Smc5/6 complex in proliferation. Cell-cycle-regulated alleles reveal Smc5/6 essential functions to segregate in G2/M. Genetic screens with generated alleles underpin roles for Smc5/6 in the metabolism of recombination structures triggered by endogenous replication stress, and in replication through natural pausing sites.