Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair
Screening human ubiquitin E2 enzymes for DSB repair functions
Nature Cell Biology
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Schmidt, C., Galanty, Y., Sczaniecka-Clift, M., Coates, J., Jhujh, S., Demir, M., Cornwell, M., et al. (2015). Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. Nature Cell Biology, 17 1458-1470. https://doi.org/10.1038/ncb3260
Ubiquitylation is crucial for proper cellular responses to DNA double-strand breaks (DSBs). If unrepaired, these highly cytotoxic lesions cause genome instability, tumourigenesis, neurodegeneration or premature ageing. Here, we conduct a comprehensive, multilayered screen to systematically profile all human ubiquitin E2- enzymes for impacts on cellular DSB responses. Applying a widely applicable approach, we use an exemplary E2 family, UBE2Ds, to identify ubiquitylation-cascade components downstream of E2s. Thus, we uncover the nuclear E3-ligase RNF138 as a key homologous recombination (HR)-promoting factor that functions with UBE2Ds in cells. Mechanistically, UBE2Ds and RNF138 accumulate at DNA-damage sites and act at early resection stages by promoting CtIP ubiquitylation and accrual. This work supplies insights into regulation of DSB repair by HR. Moreover, it provides a rich information resource on E2s that can be exploited by follow-on studies.
Alex Sossick, Nicola Lawrence and Richard Butler. Research in the S.P.J. lab is funded by Cancer Research UK Program Grant C6/A11224, the European Research Council (DDREAM), the European Community Seventh Framework Programme 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. C.K.S. was funded by a FEBS Return-to-Europe fellowship. P.B. is supported by the Emmy Noether Programme of the German Research Foundation (DFG, BE 5342/1-1).
Cancer Research UK (11224)
European Research Council (268536)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1038/ncb3260
This record's URL: https://www.repository.cam.ac.uk/handle/1810/251109