Deoxyribonucleic acid (DNA), our genetic blueprint, contains all the instructions for life. This molecule is constantly exposed to factors that can cause damage. Maintaining the integrity of this genetic information is essential for cellular function and organismal health. Without repair mechanisms, alterations to DNA can lead to serious cellular and tissue issues.
How Mismatch Repair Works
Mismatch repair (MMR) serves as a proofreading system, primarily addressing errors that arise during DNA replication. When DNA is copied, the replication machinery can insert an incorrect nucleotide or create small insertions or deletions (indels). These errors result in a mismatch, where the newly synthesized strand does not correctly pair with the template. The MMR system recognizes these abnormal base pairings or structural distortions within the DNA helix.
The process begins with recognition proteins like MutS, which bind to the mismatched base pair or indel. MutL then joins the complex, helping to identify the newly synthesized DNA strand. This distinction is crucial because the repair machinery must selectively remove the erroneous segment from the newly made strand, not the original template.
Once the new strand is identified, a segment containing the error is excised. This excision can span hundreds to thousands of nucleotides, making it a “long-patch” repair mechanism. Following excision, DNA polymerase fills the gap by synthesizing new DNA using the undamaged template strand. Finally, DNA ligase seals the remaining nicks in the sugar-phosphate backbone, restoring the DNA to its correct sequence.
How Base Excision Repair Works
Base excision repair (BER) is a distinct pathway focused on correcting single damaged or modified bases that do not significantly distort the DNA helix. This damage can originate from various sources, including reactive oxygen species, alkylating agents, or spontaneous chemical reactions. Common types of damage addressed by BER include oxidized, alkylated, and deaminated bases like uracil, which can arise from cytosine deamination.
The BER pathway initiates with a specific enzyme called DNA glycosylase. Multiple types of DNA glycosylases exist, each specialized to recognize and remove a particular type of damaged or inappropriate base. The removal of the damaged base creates an apurinic/apyrimidinic (AP) site, a location in the DNA backbone where a base is missing.
An AP endonuclease then recognizes this AP site and cleaves the DNA backbone immediately adjacent to it. Following this incision, enzymes remove the remaining sugar-phosphate residue at the AP site. DNA polymerase then fills the single-nucleotide gap with the correct base. Finally, DNA ligase seals the remaining nick in the DNA strand, completing the repair and restoring the original genetic information.
Comparing Mismatch and Base Excision Repair
Mismatch repair and base excision repair are both DNA repair pathways that target distinct types of damage and operate through different mechanisms. A primary difference lies in the nature of the errors they address. Mismatch repair primarily corrects errors that occur during DNA replication, such as mismatched base pairs or small insertions and deletions of one to several nucleotides. In contrast, base excision repair focuses on individual chemically altered or damaged bases that arise from chemical modifications or spontaneous reactions, rather than replication mistakes.
The timing and origin of the damage also differentiate these two pathways. Mismatch repair acts as a post-replication surveillance system, correcting errors during the synthesis of new DNA strands. Base excision repair, however, continuously scans the DNA for damage that can occur at any point in the cell cycle due to metabolic byproducts or environmental agents.
Their recognition mechanisms reflect the types of damage they target. Mismatch repair proteins, like MutS and MutL, recognize the abnormal geometry or structural distortions caused by incorrect base pairings or indels within the double helix. Base excision repair, conversely, relies on specific DNA glycosylases that recognize particular chemical modifications or the presence of an inappropriate base.
Another distinction is the length of the DNA segment removed during repair. Mismatch repair involves the excision of a relatively long segment of the newly synthesized DNA strand, often hundreds to thousands of nucleotides long, making it a “long-patch” repair mechanism. Base excision repair removes only the single damaged base and sometimes a very short patch of one to a few nucleotides, making it a “short-patch” repair mechanism. The initiating enzymes also differ, with MutS and MutL proteins central to mismatch repair, while DNA glycosylases initiate base excision repair.
What Happens When Repair Goes Wrong
The proper functioning of DNA repair pathways is essential for maintaining genome stability. When these repair mechanisms fail or are compromised, cells accumulate mutations. This accumulation of genetic alterations can lead to genomic instability, a state where the rate of mutations or chromosomal abnormalities is elevated.
Such genetic instability can impact cellular function and organismal health. Defective DNA repair leads to an elevated risk of developing various diseases. Defects in mismatch repair, for example, are directly linked to an inherited predisposition to certain cancers, such as Lynch syndrome. Individuals with Lynch syndrome have an increased risk of developing colorectal, endometrial, and other cancers due to mutation accumulation.
Similarly, deficiencies in base excision repair components can also contribute to genetic instability and disease susceptibility. Impaired BER can lead to an accumulation of oxidative damage and other base modifications, potentially contributing to neurodegenerative diseases or certain cancers over time. The integrity of these pathways is important for preventing cancer and other pathologies arising from DNA damage.