Base Excision Repair (BER) is a cellular process responsible for maintaining the integrity of our genetic material, DNA. It acts as a specialized repair pathway that primarily targets small, non-bulky lesions that do not significantly distort the DNA helix structure. The function of BER is to prevent errors from accumulating in the genetic code, thereby safeguarding the stability of the genome. This mechanism ensures that our cells can accurately replicate and express their genes, protecting against various cellular dysfunctions.
Types of DNA Damage Repaired
Base Excision Repair addresses common damages to individual DNA bases. These damages often arise from normal cellular metabolic processes, such as the generation of reactive oxygen species, or from exposure to environmental agents like certain chemicals or radiation. BER also handles lesions that occur through spontaneous chemical reactions within the cell.
One common type of damage repaired by BER is oxidized bases, which result from oxidative stress. A notable example is 8-oxoguanine, formed when guanine is exposed to reactive oxygen species. Another category includes alkylated bases, where alkyl groups are transferred to DNA bases, leading to lesions such as 3-methyladenine. Deaminated bases, like the conversion of cytosine to uracil, are also key targets for BER. If left unrepaired, uracil in DNA can cause mutations during replication. These damaged bases, once removed, leave behind an abasic site, also known as an AP site, which BER further processes to restore the DNA’s original sequence.
The Molecular Steps of Base Excision Repair
The process of Base Excision Repair unfolds through a series of molecular steps, each mediated by specific enzymes. This mechanism ensures the accurate removal and replacement of a damaged base, restoring the DNA strand’s integrity. The process initiates with recognition and removal of the damaged base, followed by gap filling and ligation.
DNA Glycosylase Action
The first step in BER involves DNA glycosylases, enzymes that identify and remove the damaged base. These enzymes recognize specific types of damaged or inappropriate bases and cleave the N-glycosidic bond, connecting the damaged base to the DNA’s sugar-phosphate backbone. This action results in the creation of an abasic site, where the base is missing but the backbone remains intact. There are at least 11 distinct mammalian DNA glycosylases, each with specificity for a few related lesions, sometimes with overlapping functions.
AP Endonuclease Action
Next, AP endonuclease (APE1) recognizes the abasic site and makes an incision in the DNA backbone adjacent to it, typically on the 5′-side. This creates a single-strand break, or nick, in the DNA, leaving a 3′-hydroxyl group and a 5′-deoxyribose phosphate (dRP). Some DNA glycosylases are bifunctional, meaning they also possess AP lyase activity, allowing them to cleave the DNA backbone at the abasic site without the need for a separate AP endonuclease.
Gap Filling and Ligation
Following the incision, DNA polymerase (often DNA polymerase beta (Pol β)) fills the single-nucleotide gap, using the complementary strand as a template. Pol β also possesses an intrinsic 5′-deoxyribophosphodiesterase (5′-dRPase) activity, which removes the remaining sugar fragment (dRP) from the incision site. Finally, DNA ligase seals the nick in the DNA backbone, forming a phosphodiester bond and completing the repair, restoring the DNA molecule. This entire process can be considered short-patch BER, but in some cases, a long-patch BER pathway can occur, involving the synthesis of 2-11 nucleotides and different enzymes.
Importance of Base Excision Repair for Cellular Health
Efficient Base Excision Repair is important for cellular health. Without BER, DNA damage can accumulate, leading to detrimental effects on cellular processes. This accumulation can result in mutations, permanent changes to the DNA sequence. Such mutations can disrupt gene function and cellular processes, leading to serious consequences.
The unchecked accumulation of DNA damage and mutations can lead to genomic instability, a state where the cell’s genetic material becomes prone to further alterations. Genomic instability drives various diseases, including cancer. Many studies have linked defects in BER enzymes, such as 8-oxoguanine DNA glycosylase (OGG1), to an increased risk of certain cancers. For instance, mutations in the MYH and NTHL1 genes, which are involved in BER, are associated with hereditary adenomatous polyposis syndromes.
Beyond cancer, inefficient BER has also been implicated in age-related conditions and neurodegenerative disorders. As organisms age, the activity of BER pathways can decrease in various tissues, and the amount of certain DNA lesions, such as oxidized guanine, tends to increase. This suggests a connection between declining BER efficiency and the aging process itself. Maintaining efficient BER is therefore a fundamental aspect of cellular defense, contributing significantly to preventing disease and supporting long-term health.