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SENP1 Decreases RNF168 Phase Separation to Promote DNA Damage Repair and Drug Resistance in Colon Cancer

Min Wei1,2, Xinping Huang1,2, Liming Liao1,2

  • 1State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.

Cancer Research
|June 23, 2023
PubMed

Insights

SUMOylation of RNF168 triggers liquid-liquid phase separation, hindering DNA damage repair. Sentrin/SUMO-specific protease 1 (SENP1) reverses this, promoting repair and chemotherapy resistance.

Area of Science:

  • Molecular Biology
  • Genomic Stability
  • Cancer Research

Background:

  • The DNA damage response (DDR) is crucial for maintaining genomic stability.
  • Protein posttranslational modifications, such as SUMOylation, regulate DDR.
  • RNF168 is a key E3 ubiquitin ligase involved in DNA repair pathways.

Purpose of the Study:

  • To investigate the role of RNF168 SUMOylation in the DNA damage response.
  • To identify the deSUMOylase of RNF168 and its function in DNA repair.
  • To explore the therapeutic potential of targeting the RNF168-SENP1 axis in cancer.

Main Methods:

  • Western blotting to detect SUMOylated RNF168.
  • Immunofluorescence microscopy to visualize RNF168 and 53BP1 localization.
  • Cell-based assays to assess DNA repair efficiency and chemosensitivity.
  • Analysis of patient data to correlate SENP1 expression with prognosis.

Main Results:

  • SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), impairing its recruitment to DNA damage sites.
  • RNF168-catalyzed H2A ubiquitination and 53BP1 recruitment are reduced by RNF168 LLPS.
  • Sentrin/SUMO-specific protease 1 (SENP1) deSUMOylates RNF168, preventing LLPS and promoting DNA repair.
  • High SENP1 expression in colorectal adenocarcinoma correlates with poor prognosis and chemotherapy resistance.

Conclusions:

  • SUMOylation-induced LLPS of RNF168 suppresses the DNA damage response.
  • SENP1 promotes DNA repair and cancer cell resistance to DNA damaging agents by inhibiting RNF168 LLPS.
  • SENP1 is a potential therapeutic target for enhancing chemotherapy efficacy in cancer patients.

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