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Updated: Jun 25, 2025
06:44
Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
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USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer
Yunhui Li1,2,3, Lei Li1,2, Xinshu Wang1,3
1Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Summary
The deubiquitinase USP25 promotes cancer chemoresistance by enhancing DNA repair through non-homologous end joining (NHEJ). Inhibiting USP25 or its interaction with SHLD2 sensitizes cancer cells to chemotherapy.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- DNA damage is a critical factor in cancer development and progression.
- Aberrant DNA repair mechanisms significantly impact cancer treatment outcomes and patient prognosis.
Purpose of the Study:
- To investigate the role of the deubiquitinase USP25 in DNA repair and cancer chemoresistance.
- To identify mechanisms by which USP25 influences non-homologous end joining (NHEJ) and its therapeutic implications.
Main Methods:
- Investigated USP25's role in NHEJ by examining its deubiquitinase activity on SHLD2.
- Assessed the impact of USP25 deficiency on DNA repair and class switch recombination (CSR) in mice.
- Identified TRIM25 as an E3 ligase regulating USP25 stability.
- Developed a peptide to disrupt USP25-SHLD2 interaction for therapeutic testing in patient-derived xenograft (PDX) models.
Main Results:
- USP25 deubiquitinates SHLD2, enhancing its binding with REV7 and promoting NHEJ-mediated DNA repair.
- USP25 deficiency impairs NHEJ and CSR, while its overexpression correlates with chemoresistance in colon cancer.
- TRIM25-mediated degradation of USP25 controls its levels and subsequent chemoresistance.
- A peptide disrupting USP25-SHLD2 interaction reduces tumor growth and increases chemotherapy sensitivity in PDX models.
Conclusions:
- USP25 is a key regulator of the NHEJ pathway via SHLD2, contributing to cancer chemoresistance.
- USP25 represents a promising therapeutic target for enhancing chemotherapy efficacy in various cancers.
- Targeting the USP25-SHLD2 interaction offers a novel strategy for overcoming cancer treatment resistance.
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