Since activated DNA repair prevents chemosensitivity in cancers, targeting DNA repair pathway may be a potential strategy to increase the susceptibility of cancer cells to the effects of chemotherapy drugs.[24, 25] Our results showed that knockdown USP25 increased SHLD2 ubiquitination, impaired NHEJ, and led colon cancer cells to sensitivity to chemotherapy. Here, USP25 is linked to malignant colon neoplasm.