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Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity

Nature Cell Biology volume 16, pages 1016–1026 (2014)Cite this article

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Abstract

DNA double-strand breaks (DSBs) are perhaps the most toxic of all DNA lesions, with defects in the DNA-damage response to DSBs being associated with various human diseases. Although it is known that DSB repair pathways are tightly regulated by ubiquitylation, we do not yet have a comprehensive understanding of how deubiquitylating enzymes (DUBs) function in DSB responses. Here, by carrying out a multidimensional screening strategy for human DUBs, we identify several with hitherto unknown links to DSB repair, the G2/M DNA-damage checkpoint and genome-integrity maintenance. Phylogenetic analyses reveal functional clustering within certain DUB subgroups, suggesting evolutionally conserved functions and/or related modes of action. Furthermore, we establish that the DUB UCHL5 regulates DSB resection and repair by homologous recombination through protecting its interactor, NFRKB, from degradation. Collectively, our findings extend the list of DUBs promoting the maintenance of genome integrity, and highlight their potential as therapeutic targets for cancer.

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Figure 1: Screen to identify DUBs connected to DSB repair or the DNA damage G2/M checkpoint.
Figure 2: Classification of screen results.
Figure 3: Classification of DUBs on the basis of localization, DSB repair defects and phylogenetic analysis.
Figure 4: Verification of screen results.
Figure 5: UCHL5 promotes HR repair.
Figure 6: UCHL5 contributes to resection by regulating EXO1 recruitment.
Figure 7: UCHL5 regulates resection by protecting NFRKB from proteasomal degradation.

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Acknowledgements

We thank all members of the S.P.J. laboratory for helpful discussions. We are grateful to A. Blackford, D. Larrieu and K. Dry for commenting on the manuscript, N. Lawrence and A. Sossick for help with microscopy, and C. Green for scientific advice. Research in the S.P.J. laboratory is funded by Cancer Research UK Program Grant C6/A11224, the European Research Council and the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core infrastructure funding was provided by Cancer Research UK Grant C6946/A14492 and Wellcome Trust Grant WT092096. S.P.J. receives a salary from the University of Cambridge, supplemented by Cancer Research UK. R.N. was funded by a Daiichi Sankyo Foundation of Life Science fellowship and Cancer Research UK Project Grant C6/A14831; C.l.S. was funded by European Molecular Biology Organization Grant ALTF 1165-2010. J.V.F. was supported by Cancer Research UK Program Grant C6/A11224 and the Ataxia Telangiectasia Society.

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  1. Jorrit Tjeertes

    Present address: Present address: Developmental & Molecular Pathways, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach CH-4002 Basel, Switzerland.,

Authors and Affiliations

  1. The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK

    Ryotaro Nishi, Paul Wijnhoven, Carlos le Sage, Jorrit Tjeertes, Yaron Galanty, Josep V. Forment & Stephen P. Jackson

  2. Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK

    Michael J. Clague & Sylvie Urbé

  3. The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

    Stephen P. Jackson

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Contributions

R.N. designed experiments through discussion with P.W., J.T., C.l.S., Y.G. and S.P.J.; P.W., R.N., M.J.C. and S.U. cloned human DUBs. R.N., P.W., C.l.S. and J.T. carried out the screens. P.W. and C.l.S. carried out cell cycle analyses. R.N. carried out most of the other studies with P.W.’s assistance. R.N. and S.P.J. wrote the paper. All other authors, especially P.W., commented and suggested revisions for the paper.

Corresponding author

Correspondence to Stephen P. Jackson.

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Competing interests

S.P.J. is a founder and shareholder of MISSION Therapeutics Ltd., which is developing DUB inhibitors for therapeutic applications. The other authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 UCHL5 is dispensable for resection initiation but required for full resection.

(a) Cells transfected with the indicated siRNAs were subjected to cell cycle profile analysis. Data show the means of three biologically independent experiments. The error bars indicate standard error of means. (b) Clonogenic survival assay with camptothecin (CPT). Depletion of CtIP (siCtIP) is a positive control. Data show the means of two biologically independent experiments. (c) Stable cell lines expressing GFP or GFP–UCHL5 (WT or DD) were processed for immunoblotting with indicated antibodies. Tubulin is used as a loading control. Protein levels of GFP and GFP–UCHL5 derivatives are indicated below. The modified bands detected with GFP–UCHL5 (DD) are ubiquitylated UCHL5 as revealed by IP-western blotting studies (data not shown). (d,e,f,g) Cells transfected with indicated siRNAs were treated with 1 μM of CPT for 1 h and processed for immunofluorescent staining with indicated antibodies. Nuclei were stained with DAPI. Depletion of CtIP (siCtIP) is a positive control. (f) Quantification of data shown in e. Proportion of cells with >10 RPA foci in gH2AX positive cells were calculated by counting 100 gH2AX positive cells per experiment. Data show the means of two biologically independent experiments. (h) Kinetics of GFP–CtIP accumulation at DNA damage sites was assessed in cells transfected with indicated siRNAs. Signal intensity of GFP–CtIP at DNA damage sites relative to the unirradiated area was quantified Data show the means of two biologically independent experiments. (i) Cells transfected with the individual or indicated combinations of siRNAs were processed for quantitative resection assays. Data show the means of two biologically independent experiments. Scale bars indicate 10 μm.

Supplementary Figure 2 UCHL5 depletion does not result in general proteasome dysfunction.

(a) Cells treated with indicated siRNAs or proteasome inhibitor MG132 (10 μM for 6 h) were processed for immunoblotting with indicated antibodies. (b) U2OS cells stably expressing GFP-53BP1 transfected with indicated siRNAs were mock irradiated (−IR) or irradiated with 5 Gy of IR followed by 1 h incubation (+IR). Depletion of RNF8 or PSMD14 and MG132 treatment (10 μM for 1 h) were positive controls. Scale bar indicates 10 μm. (c) Quantitative resection assay with MG132 treatment (10 μM for 1 h). Data show the means of two biologically independent experiments. (d) Quantitative resection assay with indicated siRNAs. Data show the means of two biologically independent experiments. (e) Cells treated with indicated siRNAs or MG132 (10 μM for 6 h) were processed for immunoblotting with indicated antibodies.

Supplementary Figure 3 UCHL5 protects NFRKB from proteasomal turnover.

(a) GFP or GFP–UCHL5 (WT or DD) expressing cells were subjected to immunoprecipitation with an anti-GFP antibody, followed by immunoblotting with the indicated antibodies. (b) Cells transfected with indicated siRNAs were subjected to RT-qPCR for NFRKB mRNA. NFRKB depletion (siNFRKB) is a positive control. Data show the means of two biologically independent experiments. (c) Cells transfected with indicated siRNAs were processed for immunoblotting with indicated antibodies. (d) GFP–NFRKB expressing cells transfected with indicated siRNAs were treated or mock treated with MG132 (10 μM for 6 h) and processed for immunoblotting with indicated antibodies. Brackets indicate modified forms of NFRKB. Tubulin and histone H2AX are loading controls. (e) Stable cell lines expressing GFP or GFP–NFRKB were processed for immunoblotting with indicated antibodies. (f) Input fractions corresponding to Fig. 7d. (g) In vitro deubiquitylation assay with recombinant GST-tagged UCHL5 and human cell derived NFRKB modified with HA-tagged ubiquitin.

Supplementary Figure 4 NFRKB depletion results in defective resection similar to UCHL5 depletion.

(a) Stable cell lines expressing GFP or GFP–NFRKB were transfected with indicated siRNAs and subjected to immunoblotting analysis with indicated antibodies. (b,c,d) U2OS cells transfected with indicated siRNAs were treated with CPT (1 μM for 1 h) and subjected to immunofluorescent staining with indicated antibodies (b,c) or quantitative DNA-end resection assays with anti-RPA2 antibody. Data show the means of two biologically independent experiments. (d) Scale bar indicates 10 μm. (c) Quantification of data shown in b. Population of cells with >10 RPA foci in γH2AX positive cells were calculated by counting 100 γH2AX positive cells per experiment Data show the means of two biologically independent experiments. (e) U2OS cells transfected with indicated siRNAs were irradiated with 5 Gy IR and 8 h after irradiation, subjected to immunofluorescent staining with anti-γH2AX and anti-RAD51 antibodies. Populations of cells with >5 RAD51 foci colocalized with γH2AX were plotted by counting 100 cells per experiment. Data show the means of two biologically independent experiments. (f) U2OS cells transfected with indicated siRNAs were treated with CPT (1 μM for 1 h) and subjected to immunoblotting analysis with indicated antibodies. (g) Cells transfected with indicated siRNAs were subjected to cell cycle profile analysis. Data show the means of two biologically independent experiments. (h) U2OS cells transfected with indicated siRNAs were processed for immnuoblotting with indicated antibodies. (i) U2OS cells transfected with indicated combinations of siRNAs were processed for immnuoblotting with indicated antibodies. (j) U2OS cells transfected with indicated siRNAs were treated with 1 μM of CPT for 1 h and processed for immunoblotting with indicated antibodies. (k) Kinetics of GFP–EXO1 accumulation at DNA damage sites was assessed in cells transfected with indicated siRNAs. Signal intensity of GFP–EXO1 at DNA damage sites relative to the unirradiated area was quantified. Data show the means of two biologically independent experiments. (l) Input fractions corresponding to Fig. 7k. Arrows indicate NFRKB protein band. Tubulin is used as a loading control.

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Nishi, R., Wijnhoven, P., le Sage, C. et al. Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nat Cell Biol 16, 1016–1026 (2014). https://doi.org/10.1038/ncb3028

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