Phosphorylation of SMURF2 by ATM exerts a negative feedback control of DNA damage response

Timely repair of DNA double-strand breaks (DSBs) is essential to maintaining genomic integrity and preventing illnesses induced by genetic abnormalities.  We previously demonstrated that the E3 ubiquitin ligase SMURF2 plays a critical tumor suppressing role via its interaction with ring finger protein 20 (RNF20) in shaping chromatin landscape and preserving genomic stability.  However, the mechanism that mobilizes SMURF2 in response to DNA damage remains unclear. Using biochemical approaches and mass spectrometry analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at S384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase and this phosphorylation is required for its interaction with RNF20.  We demonstrate that a SMURF2 mutant with an S384A substitution has reduced capacity to ubiquitinate RNF20 while promoting Smad3 ubiquitination unabatedly.  More importantly, mouse embryonic fibroblasts (MEFs) expressing the SMURF2 S384A mutant show a weakened ability to sustain the DSB response compared to those expressing wild type SMURF2 following etoposide treatment. These data indicate that SMURF2-mediated RNF20 ubiquitination and degradation controlled by ATM-induced phosphorylation at S384 constitutes a negative feedback loop that regulates DSB repair. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

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