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UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function

Tianyi Zhang1, Janet Cronshaw1, Nnennaya Kanu1

  • 1Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;

Proceedings of the National Academy of Sciences of the United States of America
|August 6, 2014
PubMed

Insights

The E3 ubiquitin ligase UBR5 targets ATMIN for ubiquitination, promoting ATM kinase signaling after DNA damage. This process is crucial for DNA repair and cell survival following ionizing radiation.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • DNA damage response

Background:

  • ATM kinase signaling is critical for DNA damage response, mediated by the MRN complex and ATMIN.
  • NBS1 and ATMIN compete for ATM binding, but the mechanism for pathway selection is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating ATM pathway selection between MRN and ATMIN in response to ionizing radiation.
  • To identify key regulators of ATM activation following DNA damage.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • In vitro ubiquitination assays to assess UBR5 activity.
  • Site-directed mutagenesis to investigate ATMIN ubiquitination.
  • Analysis of ATM and NBS1 foci formation in response to ionizing radiation.

Main Results:

  • UBR5 interacts with ATMIN and ubiquitinates it at lysine 238 in an IR-dependent manner.
  • UBR5-mediated ATMIN ubiquitination reduces ATMIN-ATM interaction, favoring MRN-ATM signaling.
  • UBR5 deficiency or ATMIN K238 mutation impairs ATM activation, checkpoint signaling, and increases radiosensitivity.

Conclusions:

  • UBR5-mediated ATMIN ubiquitination is a critical regulatory step for ATM pathway selection and activation after DNA damage.
  • This mechanism ensures efficient DNA repair and cellular radiosensitivity.

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