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PMID:14634210

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Citation

Wang, H, Yang, Y, Schofield, MJ, Du, C, Fridman, Y, Lee, SD, Larson, ED, Drummond, JT, Alani, E, Hsieh, P and Erie, DA (2003) DNA bending and unbending by MutS govern mismatch recognition and specificity. Proc. Natl. Acad. Sci. U.S.A. 100:14822-7

Abstract

DNA mismatch repair is central to the maintenance of genomic stability. It is initiated by the recognition of base-base mismatches and insertion/deletion loops by the family of MutS proteins. Subsequently, ATP induces a unique conformational change in the MutS-mismatch complex but not in the MutS-homoduplex complex that sets off the cascade of events that leads to repair. To gain insight into the mechanism by which MutS discriminates between mismatch and homoduplex DNA, we have examined the conformations of specific and nonspecific MutS-DNA complexes by using atomic force microscopy. Interestingly, MutS-DNA complexes exhibit a single population of conformations, in which the DNA is bent at homoduplex sites, but two populations of conformations, bent and unbent, at mismatch sites. These results suggest that the specific recognition complex is one in which the DNA is unbent. Combining our results with existing biochemical and crystallographic data leads us to propose that MutS: (i) binds to DNA nonspecifically and bends it in search of a mismatch; (ii) on specific recognition of a mismatch, undergoes a conformational change to an initial recognition complex in which the DNA is kinked, with interactions similar to those in the published crystal structures; and (iii) finally undergoes a further conformational change to the ultimate recognition complex in which the DNA is unbent. Our results provide a structural explanation for the long-standing question of how MutS achieves mismatch repair specificity.

Links

PubMed PMC299810 Online version:10.1073/pnas.2433654100

Keywords

Adenosine Triphosphatases/chemistry; Adenosine Triphosphate/chemistry; Bacterial Proteins/chemistry; Base Pair Mismatch; Binding Sites; Crystallography, X-Ray; DNA/chemistry; DNA/metabolism; DNA Fragmentation; DNA Repair; DNA-Binding Proteins/chemistry; Dimerization; Escherichia coli/metabolism; Escherichia coli Proteins; Image Processing, Computer-Assisted; Microscopy, Atomic Force; Models, Chemical; Models, Genetic; MutS DNA Mismatch-Binding Protein; Normal Distribution; Nucleic Acid Conformation; Protein Binding; Protein Conformation; Proteins/chemistry

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

ECOLI:MUTS

acts_upstream_of_or_within

GO:0006298: mismatch repair

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

ECOLI:MUTS

involved_in

GO:0006298: mismatch repair

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

ECOLI:MUTS

enables

GO:0008301: DNA binding, bending

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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