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The multifaceted mismatch-repair system

Key Points

  • The mismatch repair (MMR) system is one of the most important guardians of genomic integrity. It improves the fidelity of DNA replication, aborts illegitimate recombination and affects the outcome of several other processes of DNA metabolism.

  • The malfunction of MMR gives rise to a mutator phenotype and microsatellite instability. MMR defects in humans lead to cancer of the colon, endometrium and ovary. In mice, the predominant malignancies are lymphomas and late-onset gastrointestinal tumours.

  • The MMR process involves a complex interplay of MMR-specific proteins with the replication and/or recombination machinery. It is activated by the binding of the mismatch-recognition factors, MutSα and MutSβ, to substrates that contain base?base mismatches and insertion/deletion loops that arise during recombination or from errors of DNA polymerases.

  • The ATP-dependent recruitment of MutL homologues to the mismatch-bound complex is followed by the exonuclease-mediated degradation of the error-containing strand. Once the mismatch had been removed, resynthesis of the degraded region by a DNA polymerase, followed by sealing of the remaining nick by DNA ligase, completes the repair process.

  • MMR proteins play an important role in DNA-damage processing and signalling. MMR-deficient cells are resistant to death that is induced by several important chemotherapeutic agents.

  • In recent years, the MMR system has emerged as a modifier of enigmatic processes of DNA metabolism such as somatic hypermutation, class-switch recombination and triplet-repeat expansion. The role of MMR proteins in these processes remains obscure.

Abstract

By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude. Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion. This article reviews our current understanding of this multifaceted DNA-repair system in human cells.

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Figure 1: Postreplicative mismatch repair.
Figure 2: The MutS sliding clamp and its activation.
Figure 3: The reconstituted human mismatch-repair system.
Figure 4: Mismatch repair in DNA-damage signalling.
Figure 5: Mismatch repair in gene conversion.

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Acknowledgements

I would like to thank L. Stojic for her invaluable contribution to this article and to my other colleagues and co-workers for numerous fruitful and stimulating discussions. I apologize to those whose work was not cited here due to space limitations. The generous support of the Bonizzi?Theler Stiftung, the European Community, the Swiss National Science Foundation, Swiss Bridge and UBS AG bank is also gratefully acknowledged.

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Glossary

Microsatellite instability

Alterations in the length of short repetitive sequences (microsatellites), which can be detected by the appearance of new bands after PCR amplification of microsatellite DNA from MMR-deficient cells, or tumours, that were not present in PCR products of the corresponding DNA from normal cells.

Heteroduplex

A DNA duplex formed by association between two homologous but non-identical strands, or a duplex that contains one or several mismatches that arose during replication.

Okazaki fragments

Fragments of 200?1000 nucleotides in length that are generated on the lagging strand during replication. They contain short RNA sequences at their 5′ termini, which are made by the primase complex. During the later stages of replication, the RNA sequences are removed and the Okazaki fragments are joined together to form a continuous strand.

Walker ATP-binding motif

A protein fold consisting of 200 amino-acid residues that is found in many DNA-repair proteins. The nucleotide-binding domain consists of three conserved motifs; the type A and B motifs are the most highly conserved.

Sliding clamp

A protein complex that encircles DNA and allows it to pass freely through the hole in its centre. The term was first coined to describe the β-subunit of E. coli DNA polymerase III and proliferating cell nuclear antigen (PCNA), which tether DNA polymerases to DNA, thereby increasing their processivity (that is, the number of nucleotides that are incorporated into DNA per polymerase?template binding event).

Unimolecular nucleophilic substitution

(SN1). Methylating agents of the SN1 type transfer the carbonium ion CH3+ to electron-rich centres such as the exocyclic oxygen or nitrogen atoms of DNA bases. These reagents give rise to 10-fold higher levels of O6-methylguanine in DNA than SN2-type (bimolecular) agents.

Nucleotide-excision repair

(NER). A DNA-repair process in which a small region of the DNA strand that surrounds a bulky DNA lesion, such as a UV-induced pyrimidine dimer, is recognized, removed and replaced. NER has two branches: transcription-coupled repair efficiently removes damage from transcribed strands of active genes, and global repair removes damage from the rest of the genome.

Homeologous

In this context, the term 'homeologous' describes DNA sequences that are similar, such as those that encode the same protein in different organisms, but that are too far diverged to recombine with each other under normal circumstances. Certain homeologous sequences have been shown to recombine when MMR is inactive.

Non-homologous end joining

(NHEJ). The main pathway that is used, predominantly in the G1 phase of the cell cycle, to repair chromosomal DNA double-strand breaks in somatic cells. NHEJ is error prone because it leads to the joining of random ends and to the loss of genetic information through end resection and trimming.

Synaptonemal complex

A structure that holds paired chromosomes together during prophase I of meiosis and that promotes genetic recombination.

Class-switch recombination

After immune cells have undergone V(D)J (variable (diversity) joining) recombination, they can change the constant region of their antibodies in response to stimulation by antigen. This results in changes in the effector functions of the antibodies. The process is initiated by the generation of double-stranded breaks in a region-specific manner, and some components of the non-homologous end joining (NHEJ) machinery, including the Ku heterodimer, have been implicated in their subsequent repair.

Somatic hypermutation

A mechanism for creating extra variability in antibody genes that occurs after V(D)J (variable (diversity) joining) recombination, by introducing point mutations, small insertions and small deletions into the V(D)J coding sequences.

D-loop

When single-stranded DNA invades a duplex and anneals with its complementary sequence, it displaces the other strand of the duplex, which forms a single-stranded loop resembling the letter D.

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Jiricny, J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7, 335–346 (2006). https://doi.org/10.1038/nrm1907

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