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Dynamic recruitment of UFM1-specific peptidase 2 to the DNA double-strand breaks regulated by WIP1

Bo Qin1,2, Jia Yu2, Fei Zhao1

  • 1Department of Oncology, Mayo Clinic, Rochester, MN 55905 USA.

Genome Instability & Disease
|August 31, 2022
PubMed

Insights

UFM1 Specific Peptidase 2 (UfSP2) fine-tunes DNA damage response by regulating ATM activation. UfSP2 is recruited to double-strand breaks through a phosphorylation-dependent mechanism involving ATM and WIP1, suppressing ATM activity.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • DNA Damage Response

Background:

  • UFM1 Specific Peptidase 2 (UfSP2) suppresses ATM activation, a key kinase in DNA damage response.
  • The precise mechanism for UfSP2 recruitment to double-strand break (DSB) sites and its role in fine-tuning the DNA damage response remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which UfSP2 is recruited to DSBs.
  • To understand how UfSP2 modulates ATM activation in response to DNA damage.

Main Methods:

  • Immunofluorescence to observe foci formation of UFL1 and UfSP2 after radiation.
  • Co-immunoprecipitation to study the interaction between UfSP2 and the MRN complex.
  • Western blotting to detect phosphorylation of UfSP2 by ATM and its dephosphorylation by WIP1.

Main Results:

  • UfSP2 foci formation is delayed compared to UFL1 foci formation post-irradiation.
  • UfSP2 binds to the MRN complex in the absence of DSBs.
  • ATM-mediated phosphorylation causes UfSP2 to dissociate from the MRN complex, and WIP1-mediated dephosphorylation facilitates UfSP2 recruitment to DSBs, where it suppresses ATM activation by deufmylating H4.

Conclusions:

  • A novel mechanism for the negative modulation of ATM activation by UfSP2 is identified.
  • UfSP2 recruitment to DSBs is regulated by a dynamic interplay between ATM phosphorylation and WIP1 dephosphorylation.
  • This regulatory mechanism fine-tunes the DNA damage response by controlling ATM activation pathways.
Keywords:
ATMUFSP2UfmylationWIP1

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