Abstract
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.
Highlights
The integrity of the genome is frequently challenged by various types of DNA damage induced by replication errors and/or environmental hazards
RESULTS Human single-stranded DNA-binding protein 1 (hSSB1) is SUMOylated by SUMO3, and the SUMOylation of hSSB1 is enhanced in response to DNA damage A series of studies have revealed the critical role of hSSB1 in DNA damage; its regulation in response to DNA damage remains poorly understood.[18,20,40]
Considering that the small ubiquitinlike modifier (SUMO) chain itself can interact with a series of proteins related to the DNA damage response (DDR), including NBS1, RPA70, TopBP1, and ATR,[37] these results indicate that SUMOylation of hSSB1 may enhance the recruitment of NBS1 to DNA damage sites in response to DNA damage
Summary
The integrity of the genome is frequently challenged by various types of DNA damage induced by replication errors and/or environmental hazards. Defects in the response to DNA damage contribute to genomic instability and tumorigenesis.[5] There are two major mechanisms deployed by cells to repair DSBs: nonhomologous end joining (NHEJ) and homologous recombination (HR).[6] NHEJ is a less complex form of repair than HR; in NHEJ, the two broken ends are joined together through ligation; this process is error prone and can be evoked during the entire cell cycle.[7,8,9] HR depends on undamaged homologous DNA, which it uses as a template to repair DSBs; it is an error-free repair pathway and is undertaken in the S or G2 phase of the cell cycle.[10] One of the early events in HR is the activation of the ATM DNA repair kinase. This kinase initiates a signaling cascade that recruits and phosphorylates downstream repair proteins.[11]
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