Role of VHL in DNA double-strand break repair and genomic instability in renal cell carcinoma

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) tumour suppressor gene is characterized by high genomic instability. However, the molecular mechanisms underlying the association between loss of VHL and genomic instability remain unclear. Here, we show that suppressor of cytokine signalling 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. We further demonstrate that the 30kDa and 19kDa isoforms of VHL have opposing roles in the DDR. Upon induction of DSBs, VHL30 activates the DDR, while VHL19 attenuates this response and is actively degraded through the proteasome to alleviate its inhibitory effect. Finally, we show that VHL30 binds heterochromatin protein 1 alpha (HP1 alpha) in the presence of DSBs and this interaction is required for the full activation of the DDR. VHL binding to HP1 alpha transiently releases it from chromatin to induce chromatin relaxation, which is predicted to allow for the access of DNA repair proteins. Remarkably, the DDR defect in VHL-null and VHL mutant cells deficient for HP1 alpha binding could be rescued in the presence of a histone deacetylase inhibitor (HDACI), suggesting that VHL activates the DDR by inducing chromatin decondensation to promote the recruitment of DNA repair factors to the lesion. Collectively, these results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.Ph