Our cells face a relentless barrage of DNA damage, most common causes come from small, non-bulky lesions such as oxidized, methylated, or deaminated bases. To fix these specific error, cell relies on Base Excision Repair (BER) pathway.
BER is primary defense mechanism against DNA damage caused by reactive oxygen species (ROS), alkylating agents, and spontaneous decay.
The Step-by-Step Mechanism
The BER pathway operates like a surgical extraction and replacement process. It typically follows these core steps:
1. Recognition and Excision by DNA Glycosylase
The process begins when a enzyme called DNA glycosylase patrols the DNA. Each glycosylase is able to recognize a specific type of damaged base (e.g., Uracil or 8-oxoguanine).
Once the lesion is found, glycosylase flips base out of helix and cleaves N-glycosyl bond—the bond connecting the base to the sugar-phosphate backbone. This leaves an AP site (Apurinic or Apyrimidinic site), also known as an abasic site.
2. Incision by AP Endonuclease
An enzyme called AP Endonuclease (APE1) recognizes this abasic site and cleave phosphodiester backbone immediately 5′ to lesion. This creates a cut in DNA, leaving a 3′-hydroxyl (OH) group and a 5′-deoxyribose phosphate (dRP) flap.
3. DNA Synthesis and Gap Filling
Depending on complexity of the damage, pathway splits into two branches:
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Short-patch BER: The most common route. DNA Polymerase beta adds a single missing nucleotide and uses its lyase activity to remove the leftover dRP flap.
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Long-patch BER: Used if the 5′ terminus is chemically modified or resistant. A DNA polymerase (usually delta or epsilon) synthesizes a string of 2–10 nucleotides, displacing old strand as a flap, which is then clipped off by FEN1 (Flap Endonuclease).
4. Ligation
The final step is sealing cut in sugar-phosphate backbone. In short-patch repair, DNA Ligase III (working with scaffold protein XRCC1) seals bond. In long-patch repair, DNA Ligase I performs stitch.
Importance
Without functional Base Excision Repair, accumulation of DNA lesions would lead to:
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Mutations: as incorrectly paired bases (like Uracil instead of Cytosine) can lead to permanent changes in genetic code during replication.
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Strand Breaks: as unrepaired AP sites are fragile and can lead to double-strand breaks, which are much more difficult for the cell to fix safely.
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Disease: as deficiencies in BER enzymes are strongly linked to neurodegenerative diseases, premature aging, and various forms of cancer.
BER vs. NER
BER handles small lesions, Nucleotide Excision Repair (NER) handles bigger damage (like UV-induced thymine dimers).
| Feature | Base Excision Repair (BER) | Nucleotide Excision Repair (NER) |
| Lesion Type | Small, non-bulky (oxidized/deaminated bases) | Bulky adducts (UV damage, chemical crosslinks) |
| Key Enzyme | DNA Glycosylase | Excinuclease complex |
| Amount Removed | Usually 1 nucleotide (short-patch) | ~24–32 nucleotide fragment |
| DNA Polymerase | Pol beta (Short-patch) | Pol delta or epsilon |