8.10:
Base Excision Repair
The most common way to repair damaged DNA is to cut out the damaged part, recopy the undamaged complementary strand and ligate, or “re-seal”, the nick. This general scheme of cut, copy, and paste follows in all types of excision mechanism.
Base excision repair, or BER, corrects small base damages caused by deamination, oxidation, or alkylation that occur spontaneously or are caused by environmental toxins.
In BER, a group of around 11 different enzymes called DNA glycosylases recognize different altered bases and catalyze their removal. The modified bases make weak base pairs that are detected by the glycolases.
Upon encountering such a weak base pair, DNA glycosylase wedges apart the neighboring base pairs and flips out the modified base. This flip allows the enzyme to interact with all facets of the base to accurately identify it.
Upon recognition, DNA glycosylase cleaves the bond between the modified DNA base and the deoxyribose, releasing the free base and leaving a gap in the DNA helix. This gap is recognized by an enzyme called AP endonuclease, or APE, which, along with another enzyme called phosphodiesterase, cuts the phosphodiester backbone within the polynucleotide chain.
The missing base in the DNA helix is filled by DNA polymerase β, which copies the correct base from the complementary strand at that position. Next, an enzyme called DNA ligase seals the remaining nick to give an intact, repaired DNA molecule.
8.10:
Base Excision Repair
One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of BER is the recognition of DNA damage, which is done by DNA glycosylases. Depending on the type of base, a specific glycosylase cuts the N-glycosidic bond between the nucleotide base and ribose, leaving the phosphate backbone of the DNA intact but creating an apurinic or apyrimidinic (AP) site. Bifunctional glycosylases make an incision in the phosphodiester chain, resulting in the formation of a 5’ or 3’ phosphate. Monofunctional glycosylases do not exhibit this property and have to depend on an AP Endonuclease to cleave the sugar-phosphate link, 5’ to the abasic site, producing a 3’OH and a 5’ deoxyribophosphate. Based on the corresponding W-C pairing, DNA polymerase inserts the correct base and uses its associated AP-lyase activity to remove the deoxyribose phosphate. The nick in the backbone is sealed by DNA ligase. Both DNA ligase III and DNA polymerase use the protein XRCC1 as a scaffold to bind the site of repair.
Mutations in the proteins of the BER pathways can lead to various types of cancer. For example, a mutation in the human glycosylase OGG1 is associated with an increased risk for lung and pancreatic cancers.
Suggested Reading
- Krokan, Hans E., and Magnar Bjørås. "Base excision repair." Cold Spring Harbor perspectives in biology 5, no. 4 (2013): a012583.
- Lindahl, Tomas, Peter Karran, and Richard D. Wood. "DNA excision repair pathways." Current opinion in genetics & development 7, no. 2 (1997): 158-169.