CSN7B defines a variant COP9 signalosome complex with distinct function in DNA damage response.
CSN7B defines a variant COP9 signalosome complex with distinct function in DNA damage response.
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DOI：
10.2139/ssrn.3593525
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发表时间：
2020-05
期刊：
影响因子：
8.8
通讯作者：
Jing Wang;D. Dubiel;Yanmeng Wu;Yabin Cheng;D. Wolf;W. Dubiel
中科院分区：
文献类型：
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作者：
Jing Wang;D. Dubiel;Yanmeng Wu;Yabin Cheng;D. Wolf;W. Dubiel
哺乳动物COP 9信号体（CSN）作为两种变体复合物存在，所述变体复合物含有未知功能特化的CSN 7A或CSN 7 B旁系同源物。构建敲除细胞，我们发现CSN 7A和CSN 7 B在cullin-RING泛素连接酶的去脱氧化中具有重叠的功能。然而，CSNCSN 7 B在DNA双链断裂（DSB）传感中具有独特的功能，选择性地需要共济失调毛细血管扩张突变（ATM）依赖性NBS 1 S343 p和γ H2 AX的形成以及丝裂霉素C和电离辐射引发的DNA损伤诱导的细胞凋亡。活细胞显微镜检查显示CSN 7 B而不是CSN 7A快速募集到DSB。CSN 7 B敲除细胞对DNA损伤的抗性通过未能使上游DSB信号传导组分去脱氧化来解释，从而导致DNA修复途径选择的转换，其中非同源末端连接的利用率高于同源重组。在小鼠中，CSN 7 B敲除肿瘤对DNA损伤诱导化疗具有抗性，从而为具有低CSN 7 B表达的肿瘤的不良预后提供了解释。
Mammalian COP9 signalosome (CSN) exists as two variant complexes containing either CSN7A or CSN7B paralogs of unknown functional specialization. Constructing knockout cells, we found that CSN7A and CSN7B have overlapping functions in the deneddylation of cullin-RING ubiquitin ligases. Nevertheless, CSNCSN7B has a unique function in DNA double-strand break (DSB) sensing, being selectively required for ataxia telangiectasia mutated (ATM)-dependent formation of NBS1S343p and γH2AX as well as DNA-damage-induced apoptosis triggered by mitomycin C and ionizing radiation. Live-cell microscopy revealed rapid recruitment of CSN7B but not CSN7A to DSBs. Resistance of CSN7B knockout cells to DNA damage is explained by the failure to deneddylate an upstream DSB signaling component, causing a switch in DNA repair pathway choice with increased utilization of non-homologous end joining over homologous recombination. In mice, CSN7B knockout tumors are resistant to DNA-damage-inducing chemotherapy, thus providing an explanation for the poor prognosis of tumors with low CSN7B expression.