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Brc1 促进复制应激时 Smc5-Smc6 的焦点积累和 SUMO 连接酶活性。

Brc1 Promotes the Focal Accumulation and SUMO Ligase Activity of Smc5-Smc6 during Replication Stress.

机构信息

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA

出版信息

Mol Cell Biol. 2019 Jan 3;39(2). doi: 10.1128/MCB.00271-18. Print 2019 Jan 15.

Abstract

As genetic instability drives disease or loss of cell fitness, cellular safeguards have evolved to protect the genome, especially during sensitive cell cycle phases, such as DNA replication. Fission yeast Brc1 has emerged as a key factor in promoting cell survival when replication forks are stalled or collapsed. Brc1 is a multi-BRCT protein that is structurally related to the budding yeast Rtt107 and human PTIP DNA damage response factors, but functional similarities appear limited. Brc1 is a dosage suppressor of a mutation in the essential Smc5-Smc6 genome stability complex and is thought to act in a bypass pathway. In this study, we reveal an unexpectedly intimate connection between Brc1 and Smc5-Smc6 function. Brc1 is required for the accumulation of the Smc5-Smc6 genome stability complex in foci during replication stress and for activation of the intrinsic SUMO ligase activity of the complex by collapsed replication forks. Moreover, we show that the chromatin association and SUMO ligase activity of Smc5-Smc6 require the Nse5-Nse6 heterodimer, explaining how this nonessential cofactor critically supports the DNA repair roles of Smc5-Smc6. We also found that Brc1 interacts with Nse5-Nse6, as well as gamma-H2A, so it can tether Smc5-Smc6 at replicative DNA lesions to promote survival.

摘要

当遗传不稳定性导致疾病或细胞适应性丧失时,细胞会进化出保护基因组的安全措施,尤其是在敏感的细胞周期阶段,如 DNA 复制。裂殖酵母 Brc1 已成为在复制叉停滞或崩溃时促进细胞存活的关键因素。Brc1 是一种多 BRCT 蛋白,在结构上与酿酒酵母 Rtt107 和人类 PTIP DNA 损伤反应因子相关,但功能上的相似性似乎有限。Brc1 是必需的 Smc5-Smc6 基因组稳定性复合物中突变的剂量抑制因子,被认为起旁路途径的作用。在这项研究中,我们揭示了 Brc1 与 Smc5-Smc6 功能之间出人意料的密切联系。Brc1 是在复制应激期间 Smc5-Smc6 基因组稳定性复合物在焦点中积累所必需的,并且对于崩溃的复制叉激活复合物的内在 SUMO 连接酶活性也是必需的。此外,我们表明 Smc5-Smc6 的染色质关联和 SUMO 连接酶活性需要 Nse5-Nse6 异二聚体,这解释了这种非必需的辅助因子如何关键地支持 Smc5-Smc6 的 DNA 修复作用。我们还发现 Brc1 与 Nse5-Nse6 以及 γ-H2A 相互作用,因此它可以将 Smc5-Smc6 固定在复制性 DNA 损伤处以促进存活。

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