The concept that diseases can be caused by aberrant cleavage of phosphodiester bonds within polynucleotides is relatively new. Elevated quantities of degraded RNA have been observed in brain tissue of patients with Alzheimer's disease and in a murine disease resembling human muscular dystrophy. Some of the thalassemias are caused by cleavage of the wrong phosphodiester bond during MRNA processing.
The aim of this proposal is to examine the possibility that some environmental toxicants act by deploymerizing RNA or DNA. Small amounts of nucleolytic metals can catalyze the destruction of biological function of polynucleotides. Interspersed throughout mitochondrial DNA are regions containing runs of RNA. The first experiments that we propose to carry out will be to determine if the mitrochondrial genome is danged due to attack my metals at these RNA sites. Work from our laboratory has shown that Pb2+ in catalytic amounts destroys m-RNA in vitro and we propose to determine if m-RNA is also destroyed in vivo. Virtually all mammalian cells contain oligomers of adenylic acid in which the AMP residues are linked by 2', 5' rather than 3', 5' phosphodiester bonds. They regulate the rate of protein synthesis by turning on a latent ribonuclease. The synthesis of 2', 5' (A)n is greatly enhanced by interferon and certain hormones. We have found that 2', 5' (A)n is degraded at pH 7.4 by Pb2+ and curiously by salts of Fe3+ and A13+ which is remarkable since ferric ion is insoluble at physiologic pH. Our next step will be to determine if Pb2+, Fe3+ and A13+ reduce the intracellular levels of 2', 5' (A)n in vivo. Since elevated levels of A13+ have been reported in brain tissue of victims of Alzheimers victims with material obtained from controls. In a different, but related vein we have observed that the excretion of aminoisobutyric acid (betaAIB) increased in lead- poisoning. Since betaAIB is a catabolite of the DNA base thymine, damage to DNA must have occurred. We want to find the site(s) within the body where the DNA damage occurred. The major toxicants that we will be examining are lead, iron and aluminum. The amount of lead in the environment is decreasing as coal consumption rises. Iron is an essential dietary component, but it is also a toxic substance. Aluminum is toxic, very abundant in nature and is being mobilized from the soil into the water supply due to the acidification of rainwater. It is also suspected of being a factor in Alzheimer's disease.
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| Siard, T J; Katze, J R; Farkas, W R (1989) Queuine is incorporated into brain transfer RNA. Neurochem Res 14:1159-64 |
| Lifsey Jr, B J; Farkas, W R; Reyniers, J P (1988) Interaction of lysinoalanine with the protein synthesizing apparatus. Chem Biol Interact 68:241-57 |
