DNA mismatch repair: molecular mechanism, cancer, and ageing

Abstract

DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

Fig. 1

Cartoon scheme for 3′-directed eukaryotic MMR. Recognition of a mismatch by MutSα (MSH2-MSH6) or MutSβ (MSH2-MSH3, not shown) and MutLα (MLH1-PMS2) results in the formation of a ternary complex whose protein-protein and protein-DNA interactions are modulated by ATP/ADP cofactors bound by MutSα and MutLα (indicated by red *). PCNA may play an important role in the recruitment of MMR proteins to the vicinity of the replication fork via a PIP motif on MSH6 and MSH3. Nicking by the endonuclease function of PMS2 stimulated by ATP, PCNA, and RFC and relevant protein-protein interactions (indicated by green arrow) may establish strand discrimination targeting repair to the newly synthesized strand. MMR is bidirectional and can be 5′-directed as well; this is not shown. HMGB1, a nonhistone chromatin protein that bends DNA also facilitates MMR in vitro at or before the excision step (not shown). Excision by EXO1 and possibly other as yet unidentified exonucleases leads to the formation of an RPA-coated single-strand gap. Resynthesis by replicative polδ and ligation restore the integrity of the duplex. See text for details.

Fig. 2

Structural model for T. aquaticus MutS bound to a mismatched DNA. The two protein monomers containing a deletion of the C-terminal 43 amino acids are shown in yellow and blue. The mismatched DNA containing a single unpaired T is shown in pink and red. Domains I and IV constitute the mismatch binding site. Two composite nucleotide binding sites reside in domain V. The H-U-H helix-u-turn-helix motif is essential for subunit dimerization.

Fig. 3

Structural model for human MutSα with HNPCC mutations. Four views of MutSα related by 90° rotations as indicated, with positions of HNPCC missense mutations indicated by spheres. Hypothetical functional classification of mutations is indicated by sphere colour (see legend). MSH2 and MSH6 are shown as light and dark grey Cα chain traces, respectively, and the DNA is coloured orange. Three clusters of surface mutations, which may correspond to sites of protein-protein interactions are indicated with dashed ovals. Reproduced with permission (Warren et al., 2007).