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SENP3介导的TIP60去SUMO化作用是DNA-PKcs活性和DNA损伤修复所必需的。

SENP3-mediated TIP60 deSUMOylation is required for DNA-PKcs activity and DNA damage repair.

作者信息

Han Yang, Huang Xin, Cao Xiaoyu, Li Yuchen, Gao Lei, Jia Jin, Li Gang, Guo Hejiang, Liu Xiaochang, Zhao Hongling, Guan Hua, Zhou Pingkun, Gao Shanshan

机构信息

Department of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing China.

School of life Sciences Hebei University Baoding China.

出版信息

MedComm (2020). 2022 Mar 22;3(2):e123. doi: 10.1002/mco2.123. eCollection 2022 Jun.

DOI:10.1002/mco2.123
PMID:35356800
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8941250/
Abstract

The activation of DNA-dependent kinase (DNA-PKcs) upon DNA damage contains a cascade of reactions, covering acetylation by TIP60, binding with Ku70/80, and autophosphorylation. However, how cells regulate TIP60-mediated acetylation of DNA-PKcs and the following DNA-PKcs activation upon DNA damage remains obscure. This present study reported that TIP60 is hyper-SUMOylated in normal conditions, but upon irradiation-induced DNA damage, small ubiquitin-like modifier (SUMO)-specific protease 3 (SENP3)-mediated deSUMOylation of TIP60 promoted its interaction with DNA-PKcs to form the TIP60-DNA-PKcs complex. We show that TIP60 SUMOylation is reduced quickly in response to DNA damage and the deSUMOylation of TIP60 by SENP3 is required for DNA-PKcs acetylation and its autophosphorylation. Comet and γH2AX immunofluorescence assay showed that knockdown of SENP3 impaired DNA damage repair. Using the NHEJ report system, we found that knockdown of SENP3 affected the efficiency of NHEJ. Further exploration using clonogenic survival assay, cell viability assay and cytoflow assay suggested that leaking SENP3 increased the sensitivity of tumour cells to serval DNA damage treatment. Overall, our findings revealed a previously unidentified role of SENP3 in regulating DNA-PKcs activity and DNA damage repair.

摘要

DNA损伤时，DNA依赖性蛋白激酶（DNA-PKcs）的激活包含一系列反应，包括TIP60介导的乙酰化、与Ku70/80的结合以及自身磷酸化。然而，细胞如何调节TIP60介导的DNA-PKcs乙酰化以及随后DNA损伤时DNA-PKcs的激活仍不清楚。本研究报道，在正常条件下TIP60高度SUMO化，但在辐射诱导的DNA损伤时，小泛素样修饰物（SUMO）特异性蛋白酶3（SENP3）介导的TIP60去SUMO化促进了其与DNA-PKcs的相互作用，形成TIP60-DNA-PKcs复合物。我们发现，响应DNA损伤时，TIP60的SUMO化迅速降低，SENP3介导的TIP60去SUMO化是DNA-PKcs乙酰化及其自身磷酸化所必需的。彗星实验和γH2AX免疫荧光实验表明，敲低SENP3会损害DNA损伤修复。使用非同源末端连接（NHEJ）报告系统，我们发现敲低SENP3会影响NHEJ的效率。使用克隆形成存活实验、细胞活力实验和细胞流式分析的进一步探索表明，渗漏SENP3会增加肿瘤细胞对几种DNA损伤处理的敏感性。总体而言，我们的研究结果揭示了SENP3在调节DNA-PKcs活性和DNA损伤修复中一个以前未被发现的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/00e99abea0bf/MCO2-3-e123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/5ccdabcb3fa9/MCO2-3-e123-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/d57cdaf01a9d/MCO2-3-e123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/a8841b2aab8e/MCO2-3-e123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/656b1f28d71a/MCO2-3-e123-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/fe0cc8c06210/MCO2-3-e123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/bd07df391863/MCO2-3-e123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/00e99abea0bf/MCO2-3-e123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/5ccdabcb3fa9/MCO2-3-e123-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/d57cdaf01a9d/MCO2-3-e123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/a8841b2aab8e/MCO2-3-e123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/656b1f28d71a/MCO2-3-e123-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/fe0cc8c06210/MCO2-3-e123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/bd07df391863/MCO2-3-e123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1b/8941250/00e99abea0bf/MCO2-3-e123-g001.jpg

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