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Updated: Dec 24, 2025
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Published on: June 26, 2020
UBC13-Mediated Ubiquitin Signaling Promotes Removal of Blocking Adducts from DNA Double-Strand Breaks
Remi Akagawa1, Hai Thanh Trinh1, Liton Kumar Saha1
1Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract:
Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA adducts from TOP2 poison-induced DSBs. However, mechanisms in MRE11 recruitment to DSB sites in G1 phase remain poorly understood. Here, we report that TOP2-DNA adducts are expeditiously removed through UBC13-mediated polyubiquitination, which promotes DSB resection in G2 phase. We found that this ubiquitin signaling is required for efficient recruitment of MRE11 onto DSB sites in G1 by facilitating localization of RAP80 and BRCA1 to DSB sites and complex formation between BRCA1 and MRE11 at DSB sites. UBC13 and MRE11 are dispensable for restriction-enzyme-induced "clean" DSBs repair but responsible for over 50% and 70% of NHEJ-dependent repair of γ-ray-induced "dirty" DSBs, respectively. In conclusion, ubiquitin signaling promotes nucleolytic removal of DSB blocking adducts by MRE11 before NHEJ.
Insights
Ubiquitin signaling, mediated by UBC13, is crucial for removing DNA double-strand break (DSB) adducts. This process ensures MRE11 nuclease can effectively repair damaged DNA before non-homologous end-joining (NHEJ).
Area of Science:
- Molecular Biology
- DNA Repair Mechanisms
- Cell Cycle Regulation
Background:
- DNA double-strand breaks (DSBs) require processing before repair via non-homologous end-joining (NHEJ).
- MRE11 nuclease is critical for removing Topoisomerase II (TOP2)-DNA adducts from DSBs.
- Mechanisms governing MRE11 recruitment to DSB sites in the G1 phase are not fully understood.
Purpose of the Study:
- To elucidate the role of ubiquitin signaling in MRE11 recruitment and DNA repair.
- To investigate the interplay between UBC13, TOP2-DNA adducts, and DSB repair in different cell cycle phases.
Main Methods:
- Investigated the role of UBC13-mediated polyubiquitination in removing TOP2-DNA adducts.
- Assessed the impact of ubiquitin signaling on MRE11, RAP80, and BRCA1 localization to DSB sites.
- Compared the repair efficiency of clean vs. dirty DSBs in the presence and absence of UBC13 and MRE11.
Main Results:
- TOP2-DNA adducts are rapidly cleared via UBC13-mediated polyubiquitination, promoting DSB resection in G2.
- Ubiquitin signaling is essential for MRE11 recruitment to G1 DSB sites by facilitating RAP80 and BRCA1 localization and complex formation.
- UBC13 and MRE11 are vital for repairing gamma-ray-induced 'dirty' DSBs, contributing significantly to NHEJ-dependent repair.
Conclusions:
- Ubiquitin signaling orchestrates the nucleolytic removal of DSB-blocking adducts by MRE11.
- This pathway is critical for efficient and accurate DNA double-strand break repair, particularly for complex lesions.
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