Modification of DNA by reducing sugars: a possible mechanism for nucleic acid aging and age-related dysfunction in gene expression.

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Abstract
Reducing sugars react nonenzymatically with protein amino groups to initiate a process called nonenzymatic browning. Long-lived proteins, such as collagen and the lens crystallins, accumulate sufficient modification in vivo that they acquire many of the chemical properties characteristic of aged proteins. Nucleic acids also can undergo nonenzymatic modification by sugars. Incubation of DNA or nucleotides with G-6-P produces spectral changes similar to those described for nonenzymatic browning proteins. The occurrence of chemical modification was verified by measuring the transfection efficiency of viral DNA after incubation with glucose and G-6-P. A loss of transfection potential occurred that was 1st order with respect to time and sugar concentration. The rate of inactivation by G-6-P was 25 times that of glucose; 8 days of incubation with 150 mM G-6-P decreased transfection by 4 orders of magnitude. G-6-P also produced strand scission in a time- and concentration-dependent manner. Glucose, G-6-P, and possibly other sugars can react with DNA to produce significant structural and biological alterations. Since nucleic acids are long-lived molecules in the resting cell, the accumulation of these addition products might be a mechanism for the decresed genetic viability characteristic of the aged organism.