Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 5, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41392-020-0172-4
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Funding
- National Key Research and Development Program of China [2016YFA0500304]
- National Nature Science Foundation in China (NSFC) [81772922, 81702890, 81530081, 31571395]
- Guangdong Natural Science Foundation Team Project [2014A030312015]
- Sci-Tech Project Foundation of Guangzhou City [201607020038]
- Natural Science Foundation of Guangdong Province [2016A030310218]
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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 PIAS2 alpha, 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.
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