Mismatch Repair and Replication Fidelity

Even a highly accurate DNA polymerase occasionally inserts the wrong nucleotide or slips at repetitive sequences. Mismatch repair is the system that corrects these post-replicative errors, recognising base-base mismatches and small insertion or deletion loops and excising and resynthesising the newly made, error-containing strand. It is a major contributor to the overall fidelity with which the genome is copied.

Definition

DNA mismatch repair is the post-replicative pathway that recognises base-base mismatches and insertion/deletion loops left after DNA synthesis, excises the segment of the newly synthesised strand containing the error, and resynthesises it, thereby correcting replication mistakes and increasing replication fidelity.

Scope

This entry covers how mismatch repair recognises replication errors, how it identifies and removes the nascent strand, and how it raises overall replication fidelity beyond what polymerase selectivity and proofreading achieve. It also notes the link between mismatch-repair failure and a mutator phenotype, as mechanistic background.

Core questions

• What errors does mismatch repair correct that proofreading misses?
• How does the system recognise a mismatch and decide which strand to excise?
• How much does mismatch repair add to overall replication fidelity?
• What happens to mutation rates when mismatch repair fails?

Key concepts

• Replication fidelity
• Base-base mismatch
• Insertion/deletion loops
• Strand discrimination
• MutS and MutL homologues
• Excision and resynthesis
• Mutator phenotype
• Microsatellite instability

Mechanisms

Replication fidelity is achieved in layers: nucleotide selectivity by the polymerase, proofreading by its exonuclease, and finally mismatch repair, which corrects errors that escape the first two steps. Recognition begins when a MutS homologue binds a mismatch or an insertion/deletion loop; a MutL homologue is then recruited, the newly synthesised strand is identified as the one to be corrected, and the error-containing segment is excised and resynthesised. Kunkel and Erie describe how this stepwise system lowers the replication error rate substantially, and Jiricny emphasises that the same machinery participates in additional functions beyond simple error correction. Strand discrimination, which ensures the new rather than the template strand is repaired, is a defining requirement of the pathway, since correcting the wrong strand would fix the error as a mutation.

Clinical relevance

Loss of mismatch repair produces a mutator phenotype and microsatellite instability, and inherited mismatch-repair defects are associated with Lynch syndrome and an increased risk of certain cancers; this entry presents those associations as mechanistic background and is not a basis for diagnosis or management of any individual.

History

The biochemistry of mismatch repair was worked out first in bacteria, where methylation of the template strand provides the signal for strand discrimination, and then extended to eukaryotes through the MutS and MutL homologues. The discovery in the 1990s that mismatch-repair genes are mutated in hereditary nonpolyposis colorectal cancer linked the pathway to human cancer predisposition and stimulated detailed mechanistic study, recognised in part by the 2015 Nobel Prize in Chemistry awarded to Paul Modrich for this work.

Key figures

• Paul Modrich
• Thomas Kunkel
• Josef Jiricny
• Dorothy Erie

Seminal works

• kunkel-erie-2005
• jiricny-2006

Frequently asked questions

How is mismatch repair different from proofreading?

Proofreading is done by the polymerase's own exonuclease during synthesis, immediately removing a wrongly inserted nucleotide, whereas mismatch repair acts afterward on errors that escaped proofreading, recognising the mismatch and excising part of the new strand.

Why must the system know which strand is new?

The mismatch involves a correct (template) base and an incorrect (newly inserted) base; repairing the template strand would convert the error into a permanent mutation, so strand discrimination directs excision to the newly synthesised strand.