URACIL-EXCISION DNA-REPAIR

Uracil residues are introduced into prokaryotic and eukaryotic deoxyribonucleic acid (DNA) as a normal physiological process during DNA synthesis, and by spontaneous chemical modification of cytosine residues in DNA; thus, the acquisition of uracil in cellular DNA is unavoidable. However, the rate of uracil accumulation may vary significantly, depending on the ratio of deoxyuridine triphosphate (dUTP) to deoxythymidine triphosphate (dTTP) in intracellular pools and on whether the cells are exposed to cytosinedeaminating agents. The biological consequences of uracil residues in DNA may have cytotoxic, mutagenic, or lethal effects. An uncontrolled accumulation of the uracil residues in DNA leads to various perturbations of molecular events, ranging from altered protein-nucleic acid interactions to uracil-DNA degradation. The importance of eliminating uracil from DNA is underscored, by the observation that the uracil-DNA repair pathway of almost every organism examined, is remarkably similar. It appears that not only is one nucleotide DNA repair evident in E. coli as well as in human cells, but also that uracil-DNA glycosylase is one of the most highly conserved polypeptides yet identified. Considerable progress has been made in our understanding of the biological processes involved in and the consequences of introducing uracil residues into DNA. Nevertheless, a number of important questions remain to be answered: (1) Does cytosine deamination play a significant role in UVinduced mutagenesis? (2) Is uracil-DNA degradation a general developmental strategy to promote programmed cell death? (3) What are the physiological consequences of defective uracil-DNA repair in mammalian cells? (4) What is the reaction mechanism of the uracil-DNA glycosylase-catalyzed hydrolysis of the N-glycosyl bond? (5) What mechanisms regulate the expression and activity of nuclear and mitochondrial uracil-DNA glycosylase during the cell cycle? (6) Do eukaryotic cells contain more than one gene for uracil-DNA glycosylase? (7) What is the relationship between the nuclear and mitochondrial forms of this enzyme? (8) Does uracil-DNA glycosylase nucleate the formation of an uracil-DNA excision repair complex on uracilcontaining DNA? (9) Why do viral genomes encode uracil-DNA glycosylase when the enzyme already exists in the host cell? (10) In addition to uracil-DNA repair, does uracil-DNA glycosylase contribute to other processes of DNA metabolism? © 1994, Academic Press Inc.