Does Mismatch Repair Favor the Leading Strand?

DNA mismatch repair (MMR) is a crucial process that ensures the fidelity of DNA replication by correcting errors that arise during the replication process. A longstanding question in the field has been whether MMR acts equally on errors that occur in the leading and lagging strands of DNA replication, or if there is a bias towards one strand or the other.

Mismatch Repair Balances Leading and Lagging Strand Fidelity

Recent research has shed light on this question, suggesting that MMR does indeed exhibit a strand-specific bias. A study published in PLOS Genetics examined the efficiency of MMR in correcting errors that occur during leading and lagging strand replication in the yeast Saccharomyces cerevisiae.
The researchers found that the efficiency of MMR varied depending on the type of mismatch and the DNA polymerase responsible for its introduction. Specifically, they observed that MMR most efficiently corrected insertion/deletion errors, which are the most potentially deleterious replication errors. Additionally, MMR was more efficient at correcting substitution mismatches introduced by the leading strand polymerase, DNA polymerase ε, compared to those introduced by the lagging strand polymerases, DNA polymerases α and δ.

Strand Discrimination Mechanisms in Mismatch Repair

The ability of MMR to distinguish between the parental and daughter strands is essential for its proper function. In bacteria like Escherichia coli, this strand discrimination is achieved through transient hemimethylation of the newly replicated DNA. However, the mechanisms of strand discrimination in eukaryotes have been less clear.
Recent evidence suggests that eukaryotic MMR may utilize replication-associated signals, such as nicks or gaps in the newly synthesized DNA, to identify the daughter strand and direct the repair machinery accordingly. A review article in the Journal of Biological Chemistry discusses how the replicative clamps, such as PCNA in eukaryotes, may play a key role in this process by mediating the asymmetric loading of MMR proteins onto the daughter strand.