2. Academic Validation
  3. RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase

RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase

  • Cell Death Differ. 2020 Apr;27(4):1383-1397. doi: 10.1038/s41418-019-0424-4.
Ying Xie  # 1 2,  Yi-Ke Liu  # 3,  Zong-Pei Guo 1,  Hua Guan 1,  Xiao-Dan Liu 1,  Da-Fei Xie 1,  Yi-Guo Jiang 3,  Teng Ma 4 5,  Ping-Kun Zhou 6 7
Affiliations

Affiliations

  • 1 Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, 100850, Beijing, China.
  • 2 Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, 410013, Changsha, China.
  • 3 Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 511436, Guangzhou, China.
  • 4 Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, 100850, Beijing, China. mateng82913@163.com.
  • 5 Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, 101149, Beijing, China. mateng82913@163.com.
  • 6 Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, 100850, Beijing, China. zhoupk@bmi.ac.cn.
  • 7 Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 511436, Guangzhou, China. zhoupk@bmi.ac.cn.
  • # Contributed equally.
PMID: 31562368 DOI: 10.1038/s41418-019-0424-4
Abstract

End resection of DNA double-strand breaks (DSBs) to form 3' single-strand DNA (ssDNA) is critical to initiate the homologous recombination (HR) pathway of DSB repair. HR pathway is strictly limited in the G1-phase cells because of lack of homologous DNA as the templates. Exonuclease 1 (EXO1) is the key molecule responsible for 3' ssDNA formation of DSB end resection. We revealed that EXO1 is inactivated in G1-phase cells via ubiquitination-mediated degradation, resulting from an elevated expression level of RING-box protein 1 (RBX1) in G1 phase. The increased RBX1 significantly prompted the neddylation of Cullin1 and contributed to the G1 phase-specific degradation of EXO1. Knockdown of RBX1 remarkedly attenuated the degradation of EXO1 and increased the end resection and HR activity in γ-irradiated G1-phase cells, as demonstrated by the increased formation of RPA32, BrdU, and RAD51 foci. And EXO1 depletion mitigated DNA repair defects due to RBX1 reduction. Moreover, increased autophosphorylation of DNA-PKcs at S2056 was found to be responsible for the higher expression level of the RBX1 in the G1 phase. Inactivation of DNA-PKcs decreased RBX1 expression, and simultaneously increased EXO1 expression and DSB end resection in G1-phase cells. This study demonstrates a new mechanism for restraining the HR pathway of DNA DSB repair in G1 phase via RBX1-prompted inactivation of EXO1.

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