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Updated: Dec 4, 2025

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

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

Liu-Ya Tang1, Adam Thomas1, Ming Zhou2

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

The Journal of Biological Chemistry
|October 24, 2020
PubMed

Insights

The ataxia telangiectasia mutated (ATM) kinase phosphorylates SMURF2, enabling its interaction with RNF20 to regulate DNA double-strand break repair. This ATM-SMURF2-RNF20 pathway is crucial for maintaining genomic stability.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA double-strand breaks (DSBs) threaten genomic integrity and can lead to disease.
  • SMURF2, an E3 ubiquitin ligase, is known to suppress tumors by interacting with RNF20, influencing chromatin and genomic stability.
  • The precise mechanism controlling SMURF2's activity during DNA damage response was previously unknown.

Purpose of the Study:

  • To elucidate the mechanism by which SMURF2 is mobilized in response to DNA damage.
  • To investigate the role of SMURF2 phosphorylation in its interaction with RNF20 and subsequent DNA repair processes.

Main Methods:

  • Biochemical approaches and mass spectrometry (MS) analysis were employed.
  • Site-directed mutagenesis was used to create a SMURF2 S384A mutant.
  • Experiments were conducted using mouse embryonic fibroblasts (MEFs) treated with etoposide.

Main Results:

  • ATM kinase phosphorylates SMURF2 at Ser384 during the DNA damage response.
  • This ATM-induced phosphorylation is essential for SMURF2's interaction with RNF20.
  • SMURF2 S384A mutant exhibits reduced RNF20 ubiquitination but normal Smad3 ubiquitination, impairing DSB repair capacity in MEFs.

Conclusions:

  • ATM-mediated phosphorylation of SMURF2 at Ser384 is a key step in regulating the SMURF2-RNF20 interaction.
  • This phosphorylation-dependent pathway forms a negative feedback loop controlling DSB repair by modulating RNF20 ubiquitination and degradation.
Keywords:
ATMDNA damage responseDNA repairH2B ubiquitinationRNF20SMURF2histone modificationphosphorylationubiquitylation (ubiquitination)

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