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Review
. 2015 Oct 30;290(44):26395-403.
doi: 10.1074/jbc.R115.660142. Epub 2015 Sep 9.

Mismatch repair

Richard Fishel  1
Affiliations
Review

Mismatch repair

Richard Fishel. J Biol Chem. .

Abstract

Highly conserved MutS homologs (MSH) and MutL homologs (MLH/PMS) are the fundamental components of mismatch repair (MMR). After decades of debate, it appears clear that the MSH proteins initiate MMR by recognizing a mismatch and forming multiple extremely stable ATP-bound sliding clamps that diffuse without hydrolysis along the adjacent DNA. The function(s) of MLH/PMS proteins is less clear, although they too bind ATP and are targeted to MMR by MSH sliding clamps. Structural analysis combined with recent real-time single molecule and cellular imaging technologies are providing new and detailed insight into the thermal-driven motions that animate the complete MMR mechanism.

Keywords: DNA mismatch repair; DNA repair; Lynch syndrome; cancer biology; hMLH1; hMSH2; hereditary non-polyposis colorectal cancer; mutagenesis; single molecule analysis; single-molecule biophysics.

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Figures

FIGURE 1.
FIGURE 1.
The mismatch repair reaction. A, illustration of the MMR excision-resynthesis process. The γ-proteobacteria components that direct strand-specific excision are shown in blue; bacterial (outside γ-proteobacteria), archaeal, and eukaryotic components are shown in black. The resynthesis on the exonuclease gap is performed by the replicative polymerase, and the remaining strand scission was sealed by DNA ligase. B, diagram of a simple MMR DNA substrate containing overlapping restriction sites containing a mismatch that result in resistance to endonuclease restriction. Strand scission-directed excision-resynthesis results in replacement of one strand and a gain of restriction sensitivity (EcoRI) that is diagnostic for which strand was used as a template.
FIGURE 2.
FIGURE 2.
The molecular switch model. A, common MSH transitions during the mismatch search, recognition, and ATP-bound sliding clamp formation for all known organisms. From left to right: mismatch searching MSH, mismatch-bound MSH, and ATP-bound MSH sliding clamp. Diffusion characteristics and dwell times are detailed above/below each transition state. See text. B, downstream interactions of γ-proteobacteria such as E. coli. 1) The formation of multiple ATP-bound MutS sliding clamps (A) attracts MutL, which diffuses along the DNA as multiple MutS·MutL complexes. 2) The interaction of one MutS·MutL complex activates MutH, which introduces a strand scission on the unmethylated strand of a GATC Dam methylation site. 3) Following MutH incision, the MutS·MutL·MutH complex spontaneously dissociates. 4) A following MutS·MutL sliding clamp complex interacts with UvrD, which is attracted to the single-strand scission and stabilizes its DNA binding. 5) The MutS·MutL clamp complex enhances the processivity of the UvrD helicase, allowing strand unwinding and presentation of the single-stranded DNA to one of the four MMR exonucleases. SSB, single-stranded binding. 6) The process in B5 is iterative until the mismatch is released, eliminating the loading of additional MutS sliding clamps. See text.
FIGURE 3.
FIGURE 3.
The molecular switch model for eukaryotes. The 5′- and 3′-excision reactions require different components, but both processes start with the loading of multiple ATP-bound MSH sliding clamps. A, 5′-excision. 1) An ATP-bound MSH sliding clamp interacts and stabilizes EXOI on the DNA at a 5′-strand scission and enhances its 5′→3′ exonuclease processivity. 2) When one MSH·EXOI complex spontaneously dissociates, a following MSH sliding clamp interacts with EXOI, restarting exonuclease digestion. 3) The binding of RPA to the nascent gap inhibits EXOI exonuclease activity until its association with a following MSH sliding clamp. This process is iterative until the mismatch is released, eliminating the loading of additional MSH sliding clamps (bottom gapped DNA). B, 3′-excision. 1) An MLH/PMS associates with an ATP-bound MSH sliding clamp that then diffuses together to PCNA bound to a 3′-strand scission (likely the 3′-end of leading strand replication). 2) The interaction between MSH·MLH/PMS and PCNA activates the intrinsic MLH/PMS endonuclease. 3) Diffusion of the MSH·MLH/PMS·PCNA complex (shown) or hand-off of the MLH/PMS to PCNA and diffusion of the MLH/PMS·PCNA complex (not shown) allows the MLH/PMS intrinsic endonuclease to introduce multiple strand scissions in the 5′-direction from the 3′-end that are substrates for the EXOI 5′-exonuclease. This process is iterative until the mismatch is released, eliminating the loading of additional MSH sliding clamps (bottom gapped DNA). See text for narrative.
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