Here we report the generation of a novel genetically and clinically relevant mouse model of sporadic renal cell carcinoma and provide for the first time mechanistic data shedding light into the early events driving renal carcinogenesis and the essential tumour suppressor role of PBRM1. Our data shows that loss of VHL induces replication stress and DNA damage accumulation, responses that curtail cellular proliferation and transformation. This evidence concerns the gene VHL and neoplasm.