In constant battle to maintain genomic integrity, your cells face an unrelenting barrage of DNA damage—from oxidative stress to spontaneous chemical decays. Primary defense mechanism against small, non-bulky base lesions is Base Excision Repair (BER) pathway.
This pathway are DNA glycosylases, that protect genome, identify damaged bases, and initiate repair process by flipping damaged base out of double helix.
How It Work
DNA glycosylases work by scanning DNA for specific lesions. Once a lesion is found, enzyme rotates nucleotide out of DNA backbone and into its active site pocket—a process called base flipping.
Enzyme then cleaves N-glycosidic bond between damaged base and sugar-phosphate backbone. This creates an apurinic/apyrimidinic (AP) site, also known as an abasic site, which signals rest of BER.
Two Functional Classes
DNA glycosylases are categorized based on their catalytic mechanism:
| Feature | Monofunctional Glycosylases | Bifunctional Glycosylases |
| Primary Action | Only cleave N-glycosidic bond. | Cleave bond AND DNA backbone. |
| Resulting Gap | Leaves an intact AP site. | Leaves a single-strand break (nick). |
| Secondary Activity | None. | Associated AP lyase activity. |
| Example | UNG (Uracil-DNA Glycosylase) | OGG1 (8-Oxoguanine Glycosylase) |
Major Types of DNA Glycosylases
1. Uracil-DNA Glycosylases (UDGs)
Perhaps most famous family, these enzymes target Uracil. While Uracil belongs in RNA, it can appear in DNA through deamination of Cytosine or accidental incorporation. If not removed, it causes a C to T mutation.
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Human Example: UNG, which is incredibly efficient at sniffing out Uracil in both single- and double-stranded DNA.
2. Oxidized Base Glycosylases
Reactive oxygen species (ROS) frequently damage DNA, often turning Guanine into 8-oxoguanine (8-oxoG). Because 8-oxoG can pair with Adenine, it is highly mutagenic.
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Human Example: OGG1 specifically recognizes and removes 8-oxoG.
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Human Example: NTH1 targets oxidized pyrimidines like thymine glycol.
3. Alkyladenine DNA Glycosylases (AAG/MPG)
These are generalists of glycosylase world. Unlike UDGs which are very specific, AAG (also known as MPG) can recognize a wide variety of alkylated bases, such as 3-methyladenine and 7-methylguanine.
4. Mismatch DNA Glycosylases
Sometimes base itself isn’t chemically damaged, but it is paired incorrectly.
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Human Example: MUTYH removes Adenine that has been incorrectly paired with 8-oxoG.
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Human Example: TDG (Thymine DNA Glycosylase) removes Thymine from G:T mismatches, which often occur when methylated Cytosine deaminates.
Clinical Significance
When these enzymes fail, the consequences are severe. Mutations in the MUTYH gene lead to MUTYH-associated polyposis (MAP), a hereditary condition that significantly increases the risk of colorectal cancer. Furthermore, because many cancer drugs work by damaging DNA of tumor cells, inhibiting specific DNA glycosylases is currently being researched as a way to make chemotherapy more effective.