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The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice

Nature Cell Biology volume 17, pages 1446–1457 (2015)Cite this article

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Abstract

DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining or homologous recombination (HR). Cell cycle stage and DNA end resection are believed to regulate the commitment to HR repair. Here we identify RNF138 as a ubiquitin E3 ligase that regulates the HR pathway. RNF138 is recruited to DNA damage sites through zinc fingers that have a strong preference for DNA with 5′- or 3′-single-stranded overhangs. RNF138 stimulates DNA end resection and promotes ATR-dependent signalling and DSB repair by HR, thereby contributing to cell survival on exposure to DSB-inducing agents. Finally, we establish that RNF138-dependent Ku removal from DNA breaks is one mechanism whereby RNF138 can promote HR. These results establish RNF138 as an important regulator of DSB repair pathway choice.

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Figure 1: Screening E3s for HR repair.
Figure 2: RNF138 is recruited to sites of DSBs through its ZNF domains.
Figure 3: RNF138 regulates Ku80 ubiquitylation in response to DNA damage.
Figure 4: ChIP of endogenous RAD51, NBS1, Ku80 and MRE11 on a unique DSB.
Figure 5: Purification and DNA-binding activity of RNF138.
Figure 6: RNF138 knockdown results in hypersensitivity to DSB-inducing agents and impairs ATR-dependent signalling.
Figure 7: RNF138 acts at the early step of the HR pathway and is upstream of CtIP.
Figure 8: RNF138 regulates DNA end resection.

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Acknowledgements

We thank J. Stark (Department of Radiation Biology, Beckman Research Institute of the City of Hope, USA), R. Baer (Department of Pathology and Cell Biology, Columbia University, USA), S. M. Janicki (The Wistar Institute, USA), O. Hammarsten (Department of Clinical Chemistry, Goteborg University, Sweden), R. Greenberg (Department of Cancer Biology, Abramson Family Cancer Research Institute, USA) and J. Chen (Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, USA) for providing valuable reagents. We thank Y. Coulombe, M.-C. Caron and W. El Shemy for technical help. We also thank the Cellular Imaging Facility at the Cross Cancer Institute for the use of microscopes and image analysis software. The Proteomics Platform of the Quebec Genomics Center provided Mass spectrometry analysis. M.J.H. is an Alberta Innovates Health Solutions Senior Scholar. I.H.I. and H.S. are recipients of the Alberta Cancer Foundation postdoctoral fellowships. M.-M.G. was a CIHR Vanier scholar and is supported by a FRQS scholarship; G.G.P. holds a Tier 1 Canada Chair in Proteomics and J.-Y.M. is a FRQS Chercheur National Investigator. This work was supported by grants from the Canadian Institute of Health Research (CIHR).

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Authors and Affiliations

  1. Departments of Oncology and Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue Edmonton, Alberta T6G 1Z2, Canada,

    Ismail Hassan Ismail, Hilmar Strickfaden, Darin McDonald, Zhizhong Xu & Michael J. Hendzel

  2. Biophysics Department, Faculty of Science, Cairo University, 12613 Giza, Egypt

    Ismail Hassan Ismail

  3. CHU de Québec Research Center, CHUL Pavilion, Oncology Axis, 2705 boul. Laurier Québec city, Québec G1V 4G2, Canada,

    Jean-Philippe Gagné & Guy G. Poirier

  4. Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, Québec G1V 0A6, Canada

    Jean-Philippe Gagné, Marie-Michelle Genois, Guy G. Poirier & Jean-Yves Masson

  5. Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon Québec City, Québec G1R 2J6, Canada,

    Marie-Michelle Genois & Jean-Yves Masson

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Contributions

I.H.I. conceived the study and carried out most of the experiments. J.-P.G. and G.G.P. performed the mass spectrometry and PAR-binding experiments. M.-M.G. carried out the DNA binding assays. Z.X. generated all DNA constructs and mutants in the study. D.M. performed some immunofluorescence experiments. H.S. generated the GFP–RAD52/RFP–H2B cells. I.H.I., J.-Y.M., G.G.P. and M.J.H. analysed the data, conceived the figures and wrote the manuscript. All authors discussed the work and manuscript.

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Correspondence to Ismail Hassan Ismail or Michael J. Hendzel.

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Integrated supplementary information

Supplementary Figure 1 The RNF138 amino acid sequence is conserved.

(A) Amino acid alignment of RNF138 from different organisms is shown. Alignments was performed using Uniprot online tools. Identical residues are highlighted in black, conserved hydrophobic resides in light grey, other conservative changes are shown in darker grey. Star symbols indicate the conserved residues. (B) Scatter plots of the flow cytometric analysis of HeLa-Fucci cells prior to and post-sorting. The target cell populations were sorted using the indicated gates. (C) Western blot analysis of extracts prepared from sorted cells. Whole-cell extracts were prepared from sorted Fucci cells and probed for Ku80, cyclin A (S/G2 marker), and tubulin (loading control) by immunoblotting.

Supplementary Figure 2 RNF138 knock down alters Ku80 retention at the sites of DNA damage.

(A) GFP-Ku80 expressing cells were either transfected with control siRNA (CTL siRNA) or one of two different RNF138 siRNA (RNF138 siRNA1 and RNF138 siRNA2) for 48 h. Recruitment of GFP-Ku80 to sites of laser-induced DNA damage after micro-irradiation in U2OS cells was monitored using time lapse microscopy. Representative images are shown. Right: The mean levels of Ku80 accumulation at sites of laser tracks was quantified using LSM software and plotted as indicated. Data show mean ± s.d.; n = 44 cells, data pooled across two independent experiments. (B) RNF138 does not target Ku80 for degradation. U2OS cells transfected with either control siRNA (CTL siRNA) or RNF138 siRNA were treated with cycloheximide (CHX, 40 μM alone or together with MG132 (MG132, 20 μM) for indicated periods. The degradation of endogenous Ku80 was analyzed by anti-Ku80 immunoblotting. (C) Efficiency of NHEJ repair in NHEJ reporter cells reconstituted with different siRNA resistant RNF138 deletion mutant constructs and transfected with control siRNA (CTL siRNA) or RNF138-specific siRNA (RNF138 siRNA). The percentage of GFP positive cells was measured using a flow cytometer. Data show the mean ± SD; n = 3 biologically independent experiments that were based on gating 20,000 in each experimental condition. Scale bars are 5 μm.

Supplementary Figure 3 RNF138 mediates Ku80 ubiquitylation in response to DNA damage in S/G2 phase of the cell cycle.

Fucci cells were either transfected with control siRNA (CTL siRNA) or RNF138 specific siRNA (RNF138 siRNA) and then sorted by flow cytometry. Cells were exposed or not exposed to DNA damage by CLM. Soluble (Sol.) and chromatin fraction (Chr.) were isolated and subjected to immunopreciptation as indicated. Images are representative of two independent experiments.

Supplementary Figure 4 Cell cycle synchronization of DR95 cells expressing Isce-I cutting site.

Cells were synchronized, DNA content analysis was done by flow cytometer using propidium iodide staining. Left: Representatives DNA content profiles were shown. Right: the percentage of cells at each phase of the cell cycle is represented in the form of a table. Images are representative of two independent experiments.

Supplementary Figure 5 RNF138 knock down inhibits Ku removal from the sites of DNA damage in S phase.

(a) Cells were treated with CPT (1 μM, for 1 h) in the presence or absence of different treatments: ATM inhibitor (10 μM, added 1 h before CPT treatment, Mirin (100 μM, added 1 h before CPT treatment) or transfected with two different RNF138 siRNA (RNF138 siRNA1 and RNF138 siRNA2) for 48 h before CPT (1 μM, for 1 h). Images were captured using Z-stacks, deconvolved using Hygens deconvolution software, Ku80 foci were quantified using MetaXpress Software and plotted on the bottom. Average Ku80 foci per cell were counted and plotted as indicated. Data show mean ± s.d.; n = 42 cells that were obtained from two biological replicates. Scale bars are 10 μm.

Supplementary Figure 6 Effect of RNF138 depletion on the recruitment of Mre11 to sites of DNA damage.

(A) U2OS cells were co-transfected with the indicated siRNAs and YFP-Mre11 plasmids for 48 h. Cells were then laser-microirradiated and the recruitment of YFP-Mre11 to the sites of DNA damage was monitored by time-lapse microscopy. Signal intensity of YFP–Mre11 at DNA damage sites relative to the unirradiated area was quantified. Representative pictures are shown. (B) Western blot analysis of cells to estimate the knock down efficiency of RNF138 are shown and served as a control. (C) The mean levels of YFP-Mre11 accumulation at sites of laser tracks was quantified using LSM software and plotted as indicated. Data show mean ± s.d.; n = 34 cells, data pooled across two biologically independent experiments. Scale bars are 10 μm.

Supplementary Figure 7 RNF138 acts downstream of Mre11 activity in the HR pathway.

(A) U2OS cells were co-transfected with the indicated siRNAs and GFP-RNF138 for 48 h. In the case of Mirin treatment, cells transfected with GFP-RNF138 were pre-treated with Mirin (100 μM, added 1 h before laser microirradiation). Cells were then laser-microirradiated and the recruitment of GFP-RNF138 to the sites of DNA damage was monitored by time-lapse microscopy. Representative pictures were shown on the left. Quantification of GFP-RNF138 signal on laser-induced DNA damage stripes were shown on the right. Data show mean ± s.d.; n = 38 cells, data pooled across two biologically independent experiments. (B) Western blot analysis of cells to estimate the knock down efficiency of Mre11 and Ku80 are shown and served as a control. (C) Cell cycle profiles of RNF138 depleted cells. U2OS cells were transfected with control siRNA (CTL siRNA) or one of two different RNF138 siRNA (RNF138 siRNA1 and RNF138 siRNA2) for 48 h. Cells were harvested and subjected to DNA content analysis using propidium iodide staining according to standard protocols. Cell cycle graphs are shown on the left. A table summarizing the cell cycle results are shown on the right. At least 20,000 cells were analyzed. Scale bars are 5 μm.

Supplementary Figure 8 RNF138 did not appreciably alter MDC1/53BP1 IRIF.

Immunostaining of U2OS cells transfected with either control (CTL) siRNA or one of two different RNF138 siRNAs (RNF138 siRNA1 and RNF138 siRNA2) for 48 h. Cells were then exposed to 2 Gy and allowed to recover for 1 h before being fixed and immunostained as indicated. Bottom: quantification of populations of cells with >15 MDC1 foci colocalized with 53BP1 were plotted by counting 100 cells per experiment. Data show mean ± s.d.; n = 200 cells, data pooled across two biologically independent experiments. (B) U2OS cells were co-transfected with either control (CTL siRNA) or one of two different RNF138 siRNA (RNF138 siRNA1 and RNF138 siRNA2) targeting RNF138 and siRNA resistant GFP-RNF138 for 48 h. Cells were harvested and nuclear extracts were prepared and immunoblotted as indicated. Scale bars are 5 μm.

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Ismail, I., Gagné, JP., Genois, MM. et al. The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat Cell Biol 17, 1446–1457 (2015). https://doi.org/10.1038/ncb3259

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