DNA bending and unbending by MutS govern mismatch recognition and specificity.

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.

authors

Wang H,Yang Y,Schofield MJ,Du C,Fridman Y,Lee SD,Larson ED,Drummond JT,Alani E,Hsieh P,Erie DA

doi

10.1073/pnas.2433654100

keywords:

subject

Has Abstract

pub_date

2003-12-09 00:00:00

pages

14822-7

issue

25

eissn

0027-8424

issn

1091-6490

pii

2433654100

journal_volume

100

pub_type

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