Uracil DNA Glycosylase (UDG), also known as UNG, is an enzyme that maintains the integrity of our genetic material. It acts as a DNA repair specialist, protecting DNA from damage. UDG’s activity is important for all known organisms, from bacteria to humans, ensuring the stability of their genetic blueprint.
The Unexpected Intruder: Uracil in DNA
DNA normally contains four bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Uracil (U) is typically found in RNA, not DNA. However, uracil can mistakenly appear in DNA through two main processes, posing a threat to genetic stability.
One common way uracil enters DNA is through the spontaneous deamination of cytosine. This chemical reaction causes cytosine to lose an amino group, transforming it into uracil. This process occurs frequently, with an estimated 70–200 cytosine bases converting to uracil per human cell per day. If this uracil remains in the DNA, it can mispair with adenine during DNA replication, leading to a C:G to T:A mutation in subsequent generations of cells.
Uracil can also be incorporated into DNA during replication when DNA polymerase mistakenly inserts deoxyuridine triphosphate (dUTP) instead of deoxythymidine triphosphate (dTTP). While cells maintain a low concentration of dUTP, errors can still occur. The presence of uracil in DNA, whether from deamination or misincorporation, can lead to incorrect base pairing and, if not corrected, result in mutations.
Uracil DNA Glycosylase: The DNA Repair Specialist
Uracil DNA Glycosylase (UDG) is the primary enzyme responsible for identifying and removing uracil from DNA. It specifically targets only uracil, not other normal DNA bases like adenine, guanine, or thymine. UDG recognizes the uracil base and excises it from the DNA strand through a unique mechanism.
The mechanism of UDG involves a “pinch-push-pull” action. UDG first binds non-specifically to the DNA, creating a kink in the backbone. This allows the enzyme to “sample” or scan the minor groove of the DNA for damaged bases. Once uracil is identified, the enzyme causes the uracil nucleotide to “flip out” of the DNA helix and into a specific active site pocket within the enzyme. Here, UDG cleaves the N-glycosidic bond, which is the link between the uracil base and the sugar-phosphate backbone, releasing the free uracil base.
The removal of the uracil base by UDG leaves behind an “AP site,” also known as an abasic site, where the base is missing but the sugar-phosphate backbone remains intact. This AP site acts as a signal for other enzymes involved in the Base Excision Repair (BER) pathway. These enzymes then cleave the DNA backbone at the AP site, remove the sugar, insert the correct nucleotide (thymine), and seal the DNA strand, completing the repair process. This ensures the DNA sequence is restored accurately.
Safeguarding Our Genetic Blueprint
The continuous activity of Uracil DNA Glycosylase maintains the stability and integrity of the genome. By constantly removing uracil from DNA, UDG prevents the accumulation of potentially harmful mutations that could arise from mispaired uracil bases. In human cells, UDG is estimated to repair between 100 to 500 damaged bases daily.
Defects or deficiencies in UDG activity can have significant consequences for human health. A compromised UDG function leads to increased mutation rates because uracil bases are not removed efficiently, allowing mutations to become permanent during DNA replication. Such increased mutation rates have been linked to a higher risk of certain conditions, including some cancers and immune deficiencies, such as Hyper-IgM syndrome type 5.
The widespread presence of UDG across all forms of life, including bacteria, archaea, and eukaryotes, underscores its evolutionary importance. This conservation highlights that removing uracil from DNA is an ancient mechanism organisms have evolved to preserve their genetic information and adapt to environmental challenges. The enzyme’s role in DNA repair demonstrates the systems that safeguard the blueprint of life.