SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites
SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites
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SUMO 化可稳定 hSSB1 并增强 NBS1 向 DNA 损伤位点的募集。
DOI：
10.1038/s41392-020-0172-4
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发表时间：
2020-06-24
影响因子：
39.3
通讯作者：
Kang, Tiebang
中科院分区：
文献类型：
--
作者：
Zhou, Liwen;Zheng, Lisi;Kang, Tiebang
人单链DNA结合蛋白1（hSSB 1）是MRN复合物有效募集至DNA双链断裂所必需的，并且对于维持基因组完整性是必不可少的。然而，hSSB 1招募NBS 1的机制仍然难以捉摸。在这里，我们确定了hSSB 1在正常条件下在K79和K94处发生SUMO化，并且这种修饰在对DNA损伤的反应中显著增强。hSSB 1的SUMO化（由PIAS 2 α和SENP 2特异性微调）不仅稳定了蛋白质，还增强了NBS 1向DNA损伤位点的募集。具有缺陷hSSB 1 SUMO化的细胞对电离辐射敏感，并且通过敲除UBC 9或添加SUMO化抑制剂来全面抑制SUMO化显著增强癌细胞对依托泊苷的敏感性。我们的研究结果表明，SUMO化作为hSSB 1的一种新的翻译后修饰，对该蛋白的功能至关重要，这表明使用SUMO化抑制剂（例如，2-D 08和ML-792）可能是一种新的策略，将有利于癌症患者接受化疗或放疗。
Human single-stranded DNA-binding protein 1 (hSSB1) is required for the efficient recruitment of the MRN complex to DNA double-strand breaks and is essential for the maintenance of genome integrity. However, the mechanism by which hSSB1 recruits NBS1 remains elusive. Here, we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage. SUMOylation of hSSB1, which is specifically fine-tuned by PIAS2α, and SENP2, not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites. Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation, and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide. Our findings reveal that SUMOylation, as a novel posttranslational modification of hSSB1, is critical for the functions of this protein, indicating that the use of SUMOylation inhibitors (e.g., 2-D08 and ML-792) may be a new strategy that would benefit cancer patients being treated with chemo- or radiotherapy.