Our genetic code is under constant assault, but cells have systems to protect it. One of these is base excision repair (BER), a process that scans DNA for specific, small-scale errors and fixes damage to individual chemical bases. This pathway corrects damage from cellular activities and environmental exposures, preserving the genome’s integrity for the health and function of the organism.
Common Causes of Base Damage
DNA is susceptible to chemical changes from the cell’s own metabolic processes. For instance, reactive oxygen species, natural byproducts of cellular respiration, can chemically modify DNA bases through oxidation. This can lead to a guanine base being converted into 8-oxoguanine, a common lesion that can cause mutations if not repaired.
Another frequent form of damage is deamination, the spontaneous loss of an amino group from a base. This event can change a base’s identity; for example, when cytosine is deaminated, it becomes uracil, a base normally found in RNA. If left uncorrected, this uracil will be read as a thymine during DNA replication, leading to a permanent mutation.
DNA bases can also be damaged by alkylation, the addition of an alkyl group from environmental chemicals and cellular metabolism. Alkylation can disrupt the normal base-pairing rules of the DNA double helix, creating a structure that must be corrected to prevent errors during replication.
The Molecular Repair Process
The base excision repair pathway is a multi-step process using specialized enzymes to correct damaged DNA bases. The first step is damage recognition, carried out by enzymes called DNA glycosylases. Each glycosylase is specialized to recognize and remove a specific type of damaged base, such as those that have been oxidized, deaminated, or alkylated. The glycosylase scans the DNA, identifies the faulty base, and cuts the bond attaching the base to the sugar-phosphate backbone, excising the damaged component.
This removal leaves behind a gap in the DNA strand known as an abasic site, or AP site. This site is then recognized by another enzyme, AP endonuclease. The AP endonuclease cuts the phosphodiester backbone of the DNA strand on one side of the AP site, creating a nick. This action prepares the DNA for the next stage of repair.
With the nick in place, the repair machinery proceeds to fill the gap. In the most common form of BER, known as short-patch repair, an enzyme called DNA polymerase β carries out two functions. It first removes the remaining sugar-phosphate portion of the AP site and then synthesizes a new, correct nucleotide into the empty space, using the opposite DNA strand as a template.
The final step is to seal the nick in the DNA backbone, which is performed by an enzyme called DNA ligase. DNA ligase creates a new phosphodiester bond that joins the newly inserted nucleotide to the rest of the DNA strand. This completes the repair, restoring the DNA to its original, undamaged state.
Health Implications of Faulty Repair
When the BER pathway does not function correctly due to genetic defects, it can have significant health consequences. The failure to repair common forms of DNA damage allows mutations to accumulate throughout the genome. This genomic instability can disrupt the function of genes that regulate cell growth and division, increasing the risk for certain types of cancer.
The accumulation of DNA damage over a lifetime is also considered a contributing factor to the aging process. The mitochondrial theory of aging suggests that if damage to mitochondrial DNA is not efficiently repaired by BER, it can lead to mitochondrial dysfunction. This decline in cellular energy production and increase in oxidative stress is linked to many age-related conditions and a decline in organ function.
There is also growing evidence linking dysfunctional BER to neurodegenerative disorders. Neurons have high metabolic rates, which generate a large amount of oxidative stress and subsequent DNA damage. Since neurons do not divide, they are heavily reliant on repair systems like BER to maintain their genomic integrity over a lifetime. Deficiencies in BER enzymes have been observed in conditions such as Alzheimer’s disease and ALS, suggesting that the inability to repair DNA lesions contributes to neuronal cell death and the progression of these diseases.
Base Excision Repair in Context
The cell possesses several distinct DNA repair systems, each tailored to handle different types of damage. Base excision repair is highly specialized for fixing small, non-helix-distorting lesions affecting a single base. This specificity distinguishes it from other repair pathways that address larger-scale problems.
One of these other systems is nucleotide excision repair (NER). Unlike BER, which targets a single damaged base, NER is responsible for removing bulky lesions that significantly distort the DNA double helix. This damage is often caused by external factors like ultraviolet radiation from sunlight, which can fuse adjacent thymine bases. NER removes a short stretch of nucleotides surrounding the bulky adduct, not just the single faulty base.
Another distinct pathway is mismatch repair (MMR). This system acts as a proofreader after DNA replication has occurred. Its primary function is to correct errors made by the DNA polymerase enzyme, such as inserting a wrong but undamaged base. While BER corrects bases that have been chemically altered, MMR fixes mismatches between standard, undamaged bases, ensuring the fidelity of newly synthesized DNA.