Our data revealed a novel mechanism of p53 deficiency-induced cisplatin resistance mediated through the p53/SIRT7/RRM2K283Cr/cleaved-PARP1 and cleaved-caspase3 axes, providing a rationale for overcoming p53 mutant/deficiency-driven chemoresistance in colon cancer cells. Here, SIRT7 is linked to colonic neoplasm.