title: K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair.
abstract: DNA repair is essential for maintaining genomic stability, and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is characterized by high genomic instability. However, the molecular mechanism underlying the association between the loss of VHL and genomic instability remains unclear. Here, we show that suppressor of cytokine signaling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. These results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: J L
authors: JL
authors: Metcalf
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: P S
authors: PS
authors: Bradshaw
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors: M
authors: M
authors: Komosa
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: S N
authors: SN
authors: Greer
authors: 1] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada [2] Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada [3] Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: M
authors: M
authors: Stephen Meyn
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: M
authors: M
authors: Ohh
mesh_terms: D004247:DNA / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004247:DNA; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D008239:Lysine