Abstract Background P53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through p53 enhancer RNA-related pathway. Methods qPCR and luciferase reporters were used to detect the expression of p53-related enhancer RNA. Nutlin3 and artificial "microRNA" were used to induce and inhibit the expression of p53 enhancer RNA, respectively. Cycle analysis and β-galactosidase assay were used to explore whether P53-bound enhancer regions 2(p53BER2) plays a role in the cell cycle and senescence response of p53-wild type (WT) renal cancer cells. The function of p53BER2 was further analyzed in vivo by nude mice. RNA sequencing was used to identify the potential target of p53BER2. Results The results showed that P53BER2 expression was down-regulated in renal cancer tissues and cell lines and could specifically express in p53-WT renal cancer cell lines. Knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in p53-WT cell lines. Further, downregulation of p53BER2 could reverse nutlin-3-induced G1 arrest and senescence in p53-WT cell lines. What is more, knockdown of p53BER2 showed a resistance to nutlin-3 treatment in Vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo, which suggested BRCA2 might mediate the function of p53BER2 in RCC. Conclusions The p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in p53-WT renal cancer cells. This further provides a novel approach and insight for the RCC and p53 research in renal cancer.