Mismatch binding, ADP–ATP exchange and intramolecular signaling during mismatch repair

Abstract

The focus of this article is on the DNA binding and ATPase activities of the mismatch repair (MMR) protein, MutS—our current understanding of how this protein uses ATP to fuel its actions on DNA and initiate repair via interactions with MutL, the next protein in the pathway. Structure-function and kinetic studies have yielded detailed views of the MutS mechanism of action in MMR. How MutS and MutL work together after mismatch recognition to enable strand-specific nicking, which leads to strand excision and synthesis, is less clear and remains an active area of investigation.

Roles for mismatch repair family proteins in promoting meiotic crossing over

“…In Saccharomyces cerevisiae , base-base and small insertion/deletion mismatches are primarily recognized by the Msh2-Msh6 complex, while large insertion/deletion loops are recognized by Msh2-Msh3 heterodimers [2,7–10] (reviewed in [11] and in [12], this issue). Though not an absolute requirement for MMR, MSH complexes can interact with the replication fork via the replicative processivity clamp (proliferating cell nuclear antigen—PCNA) [13] (and reviewed in [14,15], this issue).…”

“…Biochemical, structural, and biophysical studies have shown that MSH conformation and DNA binding are modulated by ATP binding and hydrolysis [24–34]. Differences in nucleotide affinities between MSH subunits have led to a model proposing that in the absence of a mismatch, ADP and ATP are bound to MSH subunits at high and low affinity sites, respectively, with the MSH complex showing a weak affinity for DNA due to the opening and closing of the MSH ring triggered by asymmetric ATP hydrolysis (Figure 1A) [24–34] (and reviewed in [12], this issue). When the MSH complex encounters a mismatch, ADP rapidly dissociates from one subunit.…”

Evolutionary Covariance Combined with Molecular Dynamics Predicts a Framework for Allostery in the MutS DNA Mismatch Repair Protein

“…We tested this hypothesis by performing MD simulations on some of the ADP-bound forms of MutS that occur prior to mismatch recognition: MutS-ADP S1 ATP S2 -DNA(+T), MutS-ATP S1 -ADP S2 –DNA(+T), and MutS-(ADP) 2 –DNA(+T). 14 Table S3 shows the effects of mutating sector residues R172 and I553 as well as nonsector residue Y167 to alanine on ADP-bound MutS. All ADP-bound forms of R172A and I553A show domain destabilization, but not Y167A (except ATP S1 -ADP S2 -bound MutS).…”

“…The interactions of MutS with DNA during mismatch search and recognition, and subsequent interactions with other proteins to initiate repair, are modulated by ATP binding/hydrolysis (Figure 1B). 14−23 The structures show that the mismatch-binding and ATPase sites on MutS are separated by a distance of about 70–100 Å and intervening protein domains; nonetheless, biochemical studies have revealed that these two active sites are tightly coupled through the repair process, as outlined below (reviewed in ref (14)). When not bound to a mismatch, one subunit of the dimer hydrolyzes ATP rapidly and the other slowly (fast: S1/MSH6; slow: S2/MSH2), and MutS with ADP bound to at least one subunit (S2/MSH2) is predominant in steady state.…”

Endonuclease activities of MutLα and its homologs in DNA mismatch repair

“…MutSα (MSH2-MSH6 heterodimer) and MutLα (MLH1-PMS2 heterodimer in humans and MLH1-PMS1 heterodimer in the yeast S. cerevisiae ) are required for the majority of MMR events in eukaryotes (28,36,37). MutSα is the key mismatch recognition factor (28,29,38), and MutLα acts as an endonuclease in MMR (39,40). In addition to MutSα and MutLα, MutSβ (MSH2-MSH3 heterodimer) (29,41–45), Exonuclease 1 (EXO1) (45–48), proliferating cell nuclear antigen (PCNA) (49–53), replication factor C (RFC) (53), replication protein A (RPA) (52,54,55), DNA polymerase δ (Pol δ) (44,51,56–58), MutLγ (MLH1-MLH3 heterodimer) (59–61), the 3′→5′ exonuclease activity of Pol δ (62), HMGB1 (44,63,64), DNA ligase I (44), and RNAse H2 (65,66) have also been implicated in eukaryotic MMR.…”