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VRK1 phosphorylates and protects NBS1 from ubiquitination and proteasomal degradation in response to DNA damage

Diana M Monsalve1, Ignacio Campillo-Marcos1, Marcella Salzano1

  • 1Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, E-37007 Salamanca, Spain.

Biochimica Et Biophysica Acta
|February 13, 2016
PubMed

Insights

Vaccinia-related kinase 1 (VRK1) phosphorylates NBS1, a key DNA-Damage Response (DDR) protein. This VRK1-mediated phosphorylation stabilizes NBS1, crucial for DNA repair complex assembly and function.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • DNA Repair Mechanisms

Background:

  • NBS1 is an essential early responder in the DNA-Damage Response (DDR), critical for initiating double-strand break repair.
  • The DDR pathway involves detecting DNA damage-induced chromatin alterations and assembling repair complexes.
  • NBS1 acts as a platform for recruiting and organizing repair proteins sequentially.

Purpose of the Study:

  • To investigate if the VRK1 (Vaccinia-related kinase 1) chromatin kinase influences NBS1 activation following DNA damage.
  • To explore the role of VRK1 in the early stages of the DNA-Damage Response (DDR).

Main Methods:

  • Studied the interaction and effects of VRK1 on NBS1 in cells exposed to ionizing radiation (IR) and doxorubicin.
  • Utilized VRK1 knockdown experiments to assess NBS1 foci formation and stability.
  • Examined NBS1 phosphorylation at Ser343 in ATM-deficient (ATM-/-) cells.

Main Results:

  • VRK1 forms a basal complex with NBS1 in undamaged cells.
  • VRK1 knockdown abolished IR-induced NBS1 foci, an effect observed in cell-cycle arrested and ATM-/- cells.
  • VRK1 phosphorylates NBS1 at Ser343 in response to doxorubicin or IR, particularly in ATM-/- cells, enhancing NBS1 stability and cooperating with ATM.

Conclusions:

  • VRK1 plays a significant role in NBS1 activation and stability during the DNA-Damage Response (DDR).
  • VRK1-mediated NBS1 phosphorylation is crucial for the stability of the DNA repair complex, facilitating sequential DDR steps.
  • VRK1 acts in concert with ATM to ensure efficient DNA repair.
Keywords:
DNA damage fociDNA double strand breaksNBNNibrinPhosphorylationSignaling

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