Correlated Tissue Expression of Genes of Cytoplasmic and Mitochondrial Nucleotide Metabolisms in Normal Tissues is Disrupted in Transformed Tissues

Cells maintain dual metabolic pathways to provide substrates for the replication of mitochondrial and nuclear DNA. These pathways involve two separate sets of genes in the nuclear DNA, with one set encoding proteins targeted to the mitochondrion. However, the cytoplasmic and mitochondrial metabolisms are capable of communication through the transport of deoxyribonucleosides and deoxyribonucleotides between the two subcellular compartments. Cytoplasmic and mitochondrial deoxyribonucleoside triphosphate concentrations are strongly correlated in normal cells but not in transformed cells. We were therefore interested in comparing the interactions in normal and transformed tissues between the corresponding cytoplasmic and mitochondrial metabolisms that produce deoxyribonucleoside triphosphates. We conducted an analysis of gene expression data in normal and transformed human tissues obtained from the UniGene database for a selected set of genes for proteins involved in nucleoside salvage in either the cytoplasm or mitochondria. We also included ribonucleotide reductase in our analysis due to its importance in generating deoxyribonucleoside triphosphates. This analysis revealed a large number of highly significant positive correlations between the tissue expression profiles of the genes of the mitochondrial and cytoplasmic pathways in normal tissues, indicating that in normal tissues, the two metabolisms coordinately generate deoxyribonucleoside triphosphates. In transformed tissues, this correlation structure was disrupted. Multiple correlations involving the mitochondrial nucleoside kinase gene DGUOK were statistically significantly different between normal and transformed tissues, suggesting that control of DGUOK expression relative to other cytoplasmic genes is important in transformed tissues.

Supplementary materials are available for this article. Go to the publisher's online edition of (Nucleosides, Nucleotides & Nucleic Acids) for the following free supplemental resource(s): Supplementary figure 1, Supplementary figure 2, Gandhi_Samuels_Gene_Expression_Supplemental_file.xls (Vol. 31, No. 2)]