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K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair

J L Metcalf1, P S Bradshaw2, M Komosa3

  • 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Oncogene
|March 5, 2013
PubMed

Insights

Defects in DNA repair increase cancer risk. This study reveals the von Hippel-Lindau (VHL) tumor suppressor

Area of Science:

  • Molecular biology
  • Genetics
  • Cancer research

Background:

  • DNA repair is crucial for genomic stability; its defects elevate cancer risk.
  • Clear-cell renal cell carcinoma (CCRCC) exhibits high genomic instability due to VHL gene inactivation.
  • The molecular link between VHL loss and genomic instability is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism connecting VHL loss to genomic instability in CCRCC.
  • To identify VHL's role in the DNA damage response (DDR) pathway.

Main Methods:

  • Investigated the interaction between SOCS1 and VHL following DNA double-strand breaks (DSBs).
  • Analyzed the effect of VHL K63-ubiquitylation on the DDR.
  • Assessed homologous recombination repair efficiency and DSB persistence in VHL-deficient cells.

Main Results:

  • Suppressor of cytokine signaling 1 (SOCS1) facilitates VHL's nuclear translocation and K63-ubiquitylation upon DSBs.
  • VHL loss or impaired K63-ubiquitylation weakens the DDR, reducing homologous recombination repair.
  • This leads to the accumulation of persistent DSBs.

Conclusions:

  • VHL is identified as a key component of the DDR network.
  • VHL inactivation contributes to the genomic instability observed in CCRCC.
  • Targeting VHL's DDR function may offer therapeutic strategies for CCRCC.

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