USP10 Facilitates Homologous Recombination-Mediated DNA Double-Strand Break Repair through Localization to the Nucleolus
Utani, K.; Sakasai, R.; Himeda, T.; Okuwa, T.; Iwabuchi, K.; Higuchi, M.
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Ubiquitin-specific protease 10 (USP10) is a multifunctional deubiquitinating enzyme that primarily regulates cellular stress responses, including the DNA damage response. Here, we show that USP10 is required for homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) and for the maintenance of genomic stability. USP10-depleted cells exhibit spontaneous micronuclei, impaired DSB repair following zeocin and camptothecin treatment, and reduced sister chromatid exchange. These cells are also more sensitive to irradiation and mitomycin C and display increased chromosomal abnormalities after mitomycin C treatment. Persistent RAD51 foci formation in USP10-depleted cells suggests that USP10 functions at a step downstream of RAD51 nucleofilament formation. This function of USP10 in facilitating HR repair depends on deubiquitinase activity but is independent of G3BP1/2 and PABP binding. In addition, a newly identified nucleolar localization signal is required for USP10s function in DSB repair. Together, these findings indicate that USP10 maintains genome integrity by localizing to the nucleolus and facilitating HR-mediated repair of DSBs.
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