Principles of Biochemistry Volume 3 - A. Lehninger 1985

Molecular Mechanisms of Genetic Information Transfer
More on Genes: Repair, Mutation, Recombination, and Cloning
Spontaneous deamination of cytosine to uracil can be repaired

Changes in DNA can also occur due to the chemical lability of cytosine in an aqueous environment. Cytosine residues very slowly and spontaneously lose their amino group via Hydrolysis, converting into uracil residues, which are normally absent from DNA (Fig. 30-3). If a DNA strand containing a uracil residue is replicated, the uracil fails to form sufficiently strong Hydrogen Bonds with the guanine (G) residue that serves as cytosine's normal partner. Instead, uracil tends to pair with adenine. When this new DNA strand carrying the incorrect A residue subsequently undergoes Replication, a T naturally appears at this position in the complementary strand. As a result, the daughter double-stranded DNA will contain an A-T pair in the position where a G-C pair was located in the original parental DNA prior to the damage.

This type of damage is repaired in a highly ingenious manner (Fig. 30-4). First, a specialized repair enzyme—uracil-DNA glycosylase—hydroolytically removes the incorrect base, i.e., uracil, from the damaged strand. Next, the phosphodiester bond on the 5' side of the abasic deoxyribosephosphate residue is cleaved by DNA polymerase I. Following this, DNA polymerase I inserts the correct cytidine residue at the exposed 3' end of the strand being repaired, forming a complementary pair with the guanylate residue in the undamaged strand. Finally, DNA ligase seals the repaired strand by catalyzing a covalent bond.

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Fig. 30-3. Spontaneous conversion of DNA cytosine to uracil; if left uncorrected, such a modification can cause a mutation.

The glycosylase that removes uracil from DNA must exhibit high Specificity; otherwise, it would cause far more harm than good. Fortunately, this enzyme indeed does not excise uracil from RNA nor does it cut thymine out of DNA. This circumstance suggests a hypothesis that helps explain why DNA contains thymine instead of uracil. Specifically, if normal DNA incorporated both cytosine and uracil, it would be impossible to distinguish between uracil residues originally present in the DNA and those arising from the spontaneous deamination of cytosine. Only because normal DNA contains thymine rather than uracil can the repair system recognize and remove the uracil residues generated by the spontaneous hydrolysis of cytosine.

Fig. 30-4. Repair of the spontaneous conversion of cytosine to uracil. Uracil can be enzymatically removed, after which the abasic deoxyribose phosphate is replaced with the correct deoxycytidine phosphate residue.