Metabolic clogging of mannose in human cancer cells triggers genome instability via dNTP loss

Mannose is an anti-cancer sugar that inhibits cell proliferation and enhances chemotherapy. How mannose exerts its anti-cancer activities, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced a global metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphate (dNTP) pools. This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, a pharmacological inhibition of de novo dNTP biosynthesis was sufficient to sensitize the non-engineered cells to cisplatin and inhibit dormant origin firing, suggesting the dNTP loss-induced genome instability as a major mechanism for the anti-cancer activities of mannose.