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USP7S-dependent inactivation of Mule regulates DNA damage signalling and repair

Svetlana V Khoronenkova1, Grigory L Dianov

  • 1Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.

Nucleic Acids Research
|January 1, 2013
PubMed

Insights

The deubiquitylation enzyme USP7S regulates Mule stability, preventing its degradation after DNA damage. This control is crucial for p53 accumulation and efficient DNA repair.

Area of Science:

  • Molecular biology
  • Cellular biology
  • Biochemistry

Background:

  • Mule/ARF-BP1 is an E3 ubiquitin ligase critical for DNA damage response, influencing base excision repair and p53 levels.
  • The precise regulation of Mule activity following DNA damage remains incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling Mule stability and activity in response to DNA damage.
  • To investigate the role of USP7S in the DNA damage response pathway involving Mule.

Main Methods:

  • Investigated the interaction between USP7S and Mule.
  • Analyzed Mule ubiquitination and degradation in response to DNA damage.
  • Assessed the impact of USP7S and Mule regulation on p53 levels and DNA repair efficiency.

Main Results:

  • The Ser18-containing isoform of USP7 (USP7S) deubiquitylation enzyme prevents Mule self-ubiquitylation and proteasomal degradation.
  • Downregulation of USP7S upon DNA damage triggers Mule degradation, leading to p53 accumulation.
  • Impaired Mule downregulation compromises p53 stabilization and DNA repair enzyme activity, resulting in deficient DNA repair.

Conclusions:

  • USP7S is a key regulator of Mule stability, acting as a critical checkpoint in the DNA damage response.
  • This novel mechanism highlights how Mule regulation by USP7S coordinates cellular responses to DNA damage and DNA repair processes.

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