The VHL gene is mutated in the majority of clear cell renal cell carcinoma, the most common subtype of kidney cancer. Inactivation of VHL is known to cause uncontrolled activity of the HIF family of transcription factors, which turn on oncogenic processes like angiogenesis. Surprisingly, recent research by Bert van de Kooij and Marcel van Vugt indicated that VHL has a second function. They found that VHL promotes repair of a dangerous type of DNA damage, the so-called DNA double-strand break.
Cells continuously encounter DNA double-strand breaks, which have to be faithfully repaired to prevent the acquisition of mutations. A defect in the mechanisms that repair DNA breaks accelerates mutagenesis and is therefore associated with cancer development. Interestingly, whereas defective DNA break repair drives oncogenesis, it also presents treatment opportunities. Cancer cells with defective DNA break repair are often effectively killed by drugs that even further impair DNA maintenance processes, such as inhibitors of the DNA repair enzymes PARP1/2 or PolQ.
In this project, the researchers will investigate how VHL promotes repair of DNA breaks. This will reveal the consequence of VHL inactivation in VHL-mutant kidney cancer, and give insight into how this cancer develops. They will furthermore study if VHL-mutant kidney cancer cells respond to drugs that inhibit DNA repair. Hence, this research could identify novel therapeutic strategies to treat patients with VHL-mutant kidney cancer.
