All living organisms rely on DNA as the blueprint for life, guiding cellular development and function. This genetic material faces continuous assault from various internal and external sources, leading to damage that can compromise its integrity. Cells possess sophisticated repair mechanisms to maintain their genetic code’s accuracy. One crucial pathway is Base Excision Repair (BER), a highly specialized process designed to fix specific types of DNA damage.
Common Forms of DNA Damage
DNA molecules are susceptible to damage in numerous ways. A frequent type of alteration involves oxidative damage to individual DNA bases, often resulting from reactive oxygen species generated during normal cellular metabolism or environmental exposure. For instance, guanine, one of the four DNA bases, can be oxidized to form 8-oxoguanine (8-oxoG), a modified base that can mispair with adenine during DNA replication, potentially leading to a change from a G:C base pair to a T:A base pair.
Another common alteration is deamination, where an amino group is removed from a DNA base. Cytosine, for example, can spontaneously deaminate to uracil. Uracil’s presence in DNA can lead to mutations. Alkylation, the addition of an alkyl group to a DNA base, also represents a significant source of damage that BER addresses. These modifications, if left uncorrected, can disrupt normal DNA function.
The Process of Base Excision Repair
Base Excision Repair systematically addresses damaged bases through a series of enzymatic steps. The process begins with the recognition and removal of the faulty base by a DNA glycosylase. There are multiple types of DNA glycosylases, each specifically tailored to identify and excise different forms of damaged or inappropriate bases, such as 8-oxoG or uracil. This enzyme cleaves the bond connecting the damaged base to the DNA sugar-phosphate backbone, leaving behind an “abasic site.”
Following the creation of the abasic site, an enzyme called AP endonuclease (APE1 in humans) steps in. This enzyme cuts the DNA backbone immediately adjacent to the abasic site, creating a single-strand break. This incision leaves a 3′-hydroxyl group and a 5′-deoxyribose phosphate (5′-dRP) remnant at the site of the break. Subsequently, a DNA phosphodiesterase, often a lyase activity associated with DNA polymerase beta (Pol β), removes this sugar-phosphate remnant. This prepares the site for the insertion of a new, correct nucleotide.
Once the gap is cleaned, a DNA polymerase, primarily DNA polymerase beta (Pol β) for single-nucleotide repairs, synthesizes the correct replacement nucleotide. This enzyme accurately inserts the missing base, ensuring it pairs correctly with the complementary strand. In some cases, a “long patch” repair occurs, where 2-10 nucleotides are replaced, typically involving other DNA polymerases like Pol δ and Pol ε. The final step involves DNA ligase, which forms a phosphodiester bond to seal the remaining nick in the DNA backbone, thereby completing the repair and restoring the DNA strand’s integrity. DNA ligase III is often involved in short-patch BER, while DNA ligase I participates in long-patch BER.
The Critical Role of Base Excision Repair
Base Excision Repair is paramount for maintaining cellular health. DNA damage is a constant occurrence, with estimates suggesting thousands of damaging events per cell per day. BER’s efficiency in handling small lesions is crucial for preventing the accumulation of errors in the genetic code.
When the BER pathway is impaired, damaged DNA bases accumulate, leading to increased mutations. This genomic instability has significant implications for human health. For instance, defects in BER genes have been linked to an increased susceptibility to various diseases, particularly cancer. Mutations in DNA glycosylases like MYH, for example, are known to increase the risk of colon cancer.
The pathway’s effectiveness ensures that DNA can be accurately replicated and transcribed, processes fundamental to cell division and protein synthesis. Its continuous activity safeguards the genetic blueprint, preventing the propagation of errors that could lead to cellular dysfunction, premature aging, and the development of neurodegenerative disorders. Thus, BER stands as a fundamental guardian of genomic stability, protecting the integrity of our genetic information against constant environmental and internal assaults.