DNA is constantly threatened by internal cellular processes and external environmental factors. Cells use DNA repair systems to maintain genomic integrity. The Mismatch Repair (MMR) and Base Excision Repair (BER) pathways are two distinct programs for correcting different classes of DNA lesions. These systems ensure the high fidelity of the genome by recognizing and removing damaged or incorrectly incorporated nucleotides.
Base Excision Repair Pathway
Base Excision Repair (BER) corrects small, non-helix-distorting lesions caused by chemical damage to individual bases. This damage includes spontaneous events like the oxidation of guanine, the deamination of cytosine into uracil, or the alkylation of bases. Since these subtle chemical alterations do not significantly warp the DNA helix, they require a highly targeted, base-specific repair mechanism.
The process starts with specialized enzymes called DNA glycosylases, which patrol the genome searching for damaged bases. When a lesion is found, the glycosylase flips the damaged base out of the DNA helix and cleaves the bond connecting the base to the sugar-phosphate backbone. This action excises only the damaged base, leaving behind an apurinic or apyrimidinic (AP) site.
The sugar-phosphate backbone at the AP site is then cut by an AP endonuclease, creating a break in the single strand of DNA. The resulting gap is processed through one of two sub-pathways: short-patch or long-patch repair. Short-patch BER involves DNA Polymerase \(beta\) inserting a single correct nucleotide, followed by a DNA ligase sealing the nick. The long-patch pathway replaces a segment of two to ten nucleotides, ensuring the damaged site is completely restored.
Mismatch Repair Pathway
The Mismatch Repair (MMR) pathway focuses exclusively on errors introduced during DNA replication. Despite the proofreading capabilities of DNA polymerases, mistakes occur, resulting in mismatched base pairs (e.g., A:C or G:T) or small insertion/deletion loops (indels). These replication errors create slight structural distortions in the double helix that must be corrected before cell division.
The MMR process begins when a multi-protein complex recognizes the structural abnormality caused by the mismatch. The machinery must then determine which strand—the original template or the newly synthesized daughter strand—contains the mistake. In human cells, the daughter strand is identified by transient physical breaks (nicks) and the presence of the sliding clamp protein PCNA.
Once the erroneous daughter strand is identified, an endonuclease nicks the DNA near the mismatch. A powerful exonuclease, such as EXO1, then excises a long segment of the strand, starting from the nick and proceeding past the error. This extensive removal eliminates the mistake. Finally, a DNA polymerase synthesizes a new, correct segment using the template strand, and a DNA ligase seals the final break.
Unique Molecular Components
BER relies on DNA glycosylases, a family of more than eleven proteins in humans, each highly specific for a particular type of base damage. For example, OGG1 recognizes and removes the oxidized base 8-oxo-guanine, while Thymine DNA Glycosylase (TDG) targets thymine or uracil incorrectly paired with guanine. This specialization allows BER to precisely target chemically altered bases.
In contrast, MMR relies on large, multi-protein complexes to survey the genome for structural irregularities rather than specific base chemistry. The recognition step is performed by MutS-homolog complexes. MutS \(alpha\) (MSH2 and MSH6) handles base-base mismatches and small indels, while MutS \(beta\) (MSH2 and MSH3) handles larger indels. These complexes act as molecular clamps that slide along the DNA, binding tightly when they encounter a distortion. The MutS complex then recruits the MutL-homolog complex (MLH1 and PMS2), which coordinates the repair process.
The most defining molecular difference is the mechanism of strand discrimination. BER is inherently strand-specific because only the damaged base is removed, leaving the template intact. MMR, however, must actively distinguish the newly synthesized, error-containing strand from the correct template strand to ensure accurate excision. In eukaryotes, this discrimination is facilitated by the MutL \(alpha\) complex recognizing transient single-strand breaks (nicks) in the daughter strand, often with PCNA.
Biological Impact of Failure
Failure of the BER and MMR pathways has serious consequences for cellular health and disease. A breakdown in the Mismatch Repair system is linked to cancer susceptibility. Mutations in MMR genes, particularly MLH1 and MSH2, cause Lynch Syndrome, a common inherited cancer predisposition syndrome. When MMR is dysfunctional, replication errors rapidly accumulate, leading to microsatellite instability (MSI). This hypermutational state drives tumor formation, especially in the colon and endometrium.
Defects in the Base Excision Repair pathway are associated with accumulating oxidative damage. BER is the primary defense against reactive oxygen species generated during normal metabolism. When BER capacity is compromised, such as through mutations in DNA glycosylase genes like MYH or OGG1, oxidative lesions remain unrepaired. This accumulation of damage contributes to the general aging process, increases the overall mutation load, and is linked to certain neurological disorders and specific types of polyposis.