Deoxyribonucleic acid, commonly known as DNA, serves as the genetic blueprint for all living organisms. This complex molecule constantly faces internal and external challenges that can alter its structure. To maintain the integrity of this genetic information, cells possess sophisticated DNA repair mechanisms. Base Excision Repair (BER) stands as a cellular pathway dedicated to correcting specific, frequently occurring types of DNA damage. Its primary objective is to safeguard the genome from alterations that could otherwise compromise cellular function and heredity.
Understanding DNA Damage
DNA molecules are continuously exposed to various damaging agents, both from within the cell and from the external environment. These exposures can lead to modifications of individual DNA bases. Such alterations, if left unaddressed, can interfere with DNA replication and transcription, potentially leading to errors in the genetic code.
One common type of damage involves oxidized bases, such as 8-oxoguanine, which forms when reactive oxygen species attack DNA. These reactive species are byproducts of normal cellular metabolism, like energy production. Alkylated bases, such as 3-methyladenine, result from the addition of alkyl groups to DNA bases, often from environmental chemicals or metabolic processes.
Deaminated bases also frequently occur; for instance, cytosine can spontaneously deaminate to uracil. Uracil is typically found in RNA, not DNA, making its presence in DNA an abnormal event detected by BER. These modified bases can cause incorrect base pairing during DNA replication, potentially leading to permanent changes in the DNA sequence. Abasic sites, also known as AP sites, represent locations where a base has been completely lost from the DNA backbone, leaving only the sugar and phosphate.
The Base Excision Repair Process
The Base Excision Repair pathway is a multi-step process involving a coordinated series of enzymes to restore the correct DNA sequence. This mechanism precisely targets and removes damaged or inappropriate bases without disrupting the overall DNA helix structure. The process begins with the identification and removal of the faulty base.
Recognition and Removal of the Damaged Base
DNA glycosylases are the first enzymes to act in BER, recognizing and removing specific damaged bases. DNA glycosylases are specialized to identify and remove particular types of lesions, such as oxidized purines or deaminated pyrimidines. These enzymes “flip” the damaged base out of the DNA helix, then cleave the bond connecting the base to its sugar-phosphate backbone. This action leaves behind an abasic site, where the base is missing but the sugar-phosphate backbone remains intact.
Cleavage of the AP Site
Following the creation of an abasic site, an enzyme called AP endonuclease recognizes this missing base. This enzyme then cuts the DNA backbone immediately adjacent to the abasic site. This incision creates a single-strand break in the DNA, leaving a gap ready for repair.
Gap Filling
After the incision, DNA polymerase enzymes are recruited to fill the gap with the correct nucleotide. In many cases, DNA polymerase beta (Pol β) is the primary enzyme involved, especially in a sub-pathway known as short-patch BER. This pathway replaces a single nucleotide. For larger gaps, a long-patch BER pathway is utilized. This longer repair involves DNA polymerases delta (Pol δ) and epsilon (Pol ε), often displacing a short segment of the existing strand to synthesize the new patch.
Ligation
The final step in both short-patch and long-patch BER is the sealing of the DNA strand. After the correct nucleotide(s) have been inserted by the DNA polymerase, a small break, or “nick,” remains in the backbone. DNA ligase enzymes seal this break. This action seamlessly joins the newly synthesized DNA segment with the original strand, completing the repair process and restoring the DNA’s integrity.
When BER Goes Wrong
The precise functioning of the Base Excision Repair mechanism is important for maintaining genomic stability. When components of this pathway are impaired, DNA damage can accumulate, leading to consequences for cellular health. Deficiencies in BER enzymes can result in an increased number of unrepaired lesions, which may then be converted into mutations during DNA replication.
These accumulated mutations can disrupt normal gene function and cellular processes. Such genetic alterations are associated with an increased susceptibility to certain diseases, including various forms of cancer. For example, defects in specific BER glycosylases have been linked to an elevated risk of colorectal cancer.
Impaired BER activity has also been connected to the aging process. Studies indicate that BER efficiency can decline with age in multiple tissues, contributing to the accumulation of DNA damage, such as oxidized guanine. This accumulation of unrepaired damage and subsequent mutations may play a role in the cellular dysfunction observed during aging and in age-related pathologies.