Model: Trisomy 21 accelerates CBS activity and drives mutagenesis of GATA1 toward TMD/AMkL. This model proposes that the mutational spectrum at GATA1 can be explained by increased CBS activity, occurring as a combined result of both copy number increase and an adaptive response to oxidative stress in DS. Bold letters indicate enzymes known to be up-regulated in DS. Bold arrows indicate the primary direction of the reaction. The box around 5-meTHF depicts the trapping of this metabolite in this fully reduced form. CBS indicates cytathionine-β-synthase; DHF, dihydrofolate; dTMP, deoxythymidinemonophosphate; dUMP, deoxyruidinemonophosphate; GSH, reduced glutathione; GSSG, oxidized glutathione; 8-OHdG, 8-hydroxyguanosine; PLP, pyridoxal-l-phosphate; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SOD, Cu/Zn superoxide dismutase; 5-meTHF, 5-methyltetrahydrofolate; 5,10-meTHF, 5,10-methyltetrahydrofolate; THF, tetrahydrofolate.