Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair

Christine Schmidt, Yaron Galanty, Matylda Sczaniecka-Clift, Julia Coates, Satpal Jhujh, Mukerrem Demir, Matthew Cornwell, Petra Beli, Stephen P Jackson

Research output: Contribution to journalArticlepeer-review

Abstract

Ubiquitylation is crucial for proper cellular responses to DNA double-strand breaks (DSBs). If unrepaired, these highly cytotoxic lesions cause genome instability, tumorigenesis, 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. With 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.
Original languageEnglish
Pages (from-to)1458-1470
Number of pages13
JournalNature Cell Biology
Volume17
Issue number11
Early online date26 Oct 2015
DOIs
Publication statusPublished - 26 Oct 2015

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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