Hypothetical model. The glycolytic metabolite MGO transiently disables BRCA2 tumor suppression to induce mutagenesis, bypassing the Knudson two-hit requirement. Increased glycolysis associated with cancer-associated metabolic changes, or possibly diabetes type 2, diet, or other factors, increases MGO accumulation. MGO transiently depletes BRCA2 protein below functionally adequate levels, inactivating its tumor suppressive functions, leading to induced haploinsufficiency but without permanent LOH. Cells bearing monoallelicBRCA2truncations, which express less BRCA2 protein, are more susceptible to induced haploinsufficiency than wild-type cells. MGO-inducedBRCA2haploinsufficiency precipitates a mutational signature recapitulating biallelicBRCA2loss. Episodic mutagenesis triggered by MGO or other metabolic stresses could thereby trigger macroevolutionary genomic changes, promoting cancer clonal evolution. See alsoFigures S6andS7.
