The UvrD helicase and its modulation by the mismatch repair protein MutL

Abstract

UvrD is a superfamily I DNA helicase with well documented roles in excision repair and methyl-directed mismatch repair (MMR) in addition to poorly understood roles in replication and recombination. The MutL protein is a homodimeric DNA-stimulated ATPase that plays a central role in MMR in Escherichia coli. This protein has been characterized as the master regulator of mismatch repair since it interacts with and modulates the activity of several other proteins involved in the mismatch repair pathway including MutS, MutH and UvrD. Here we present a brief summary of recent studies directed toward arriving at a better understanding of the interaction between MutL and UvrD, and the impact of this interaction on the activity of UvrD and its role in mismatch repair.

Resolving Holliday Junctions with Escherichia coli UvrD Helicase

“…Disruption of the homeologous recombination event might involve MutS and MutL directing UvrD to the HJ and facilitating unwinding of the intermediate structure. Indeed, UvrD has been shown to interact with MutL, and its activity can be modulated by the interaction with MutL (2,6). Additional work will be required to understand fully the significance of UvrD-catalyzed unwinding of HJ structures.…”

“…In the mismatch repair pathway UvrD initiates unwinding at the d(GATC)-located nick created by MutH and, together with an appropriate exonuclease, facilitates removal of the unmethylated daughter strand containing the mismatch (2,6). UvrD also participates in the UvrABC nucleotide excision repair pathway by removing the 12-13-base oligonucleotide containing a pyrimidine dimer or bulky adduct (3).…”

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…In other words, MMR can utilize a nick on either side of the mismatch. With the help of MutL, this nick in the nascent strand acts as a point of entry for helicase II that unwinds the nascent strand, a process that is facilitated by single-strand binding protein (SSB) (Matson and Robertson, 2006;Robertson et al, 2006b). This exposes the strand to digestion by one of four single-strand exonucleases having either 3′-5′ or 5′-3′ polarity: ExoI, ExoVII, ExoX, or RecJ (Burdett et al, 2001).…”

Coupling distant sites in DNA during DNA mismatch repair

“…Indeed, the observation that the eukaryotic MutL homolog Pms2 has an endonuclease activity implies that the initiation of eukaryotic MMR may be similar to the activation of MutH (18); however, if Mlh1-Pms2 does catalyze the initiating single-strand break, then how it is targeted to the newly synthesized DNA strand is unclear. Furthermore, it will be interesting to examine the effect of DNA blocks on the subsequent steps in the bacterial system such as when the UvrD helicase and the exonuclease are loaded at a single-strand break, especially because UvrD helicase activity is stimulated by MutL (19).…”

“…Second, the MutS-MutL complex has high affinity for double-strand ends (10), and if it also had a high affinity for single-strand breaks, then sliding MutS-MutL complexes could ''label'' strand-specific breaks associated with mispairs and target them for excision repair rather than ligation. Additionally, ATPbound MutL is known to help load and activate the UvrD helicase in E. coli MMR (19), and labeled breaks could directly control directionality of UvrD and subsequent strand excision. Third, sliding of the complex away from the mispair would allow other MutS-MutL complexes to be loaded onto the DNA (10).…”