To validate these observations, we experimentally converted the mutL gene between the wild-type and 6bpΔmutL in S. typhimurium and inspected the bacterial mutability status. When 6bpΔmutL was converted

to mutL, the originally highly mutable Salmonella strains regained genetic stability; when mutL was converted to 6bpΔmutL, the mutability was elevated 100-fold. Interestingly, Nutlin-3a manufacturer mutL cells were found to grow out of 6bpΔmutL cells; the new mutL cells eventually replaced the original 6bpΔmutL population. As conversion between mutL and 6bpΔmutL may occur readily during DNA replication, it may represent a previously unrecognized mechanism to modulate bacterial mutability at the population level, allowing bacteria to respond rapidly to changing environments while minimizing the risks associated with persistent hypermutability. Previously, we observed the peculiar phenomenon of genome diversification, i.e. mutants of Salmonella check details typhimurium LT7 stored at room temperature kept changing the physical structure of the genome (Liu et al., 2003). We have since concentrated on identifying the genetic basis responsible for this phenomenon, with a focus on mismatch repair (MMR) genes including mutL, mutS and mutH.

Our initial work showed that all screened S. typhimurium LT7 mutants had intact mutS and mutH genes, but a deletion was found in mutL; this genotype was designated 6bpΔmutL (Gong et al., 2007). MutL has been suggested to function as a master coordinator or molecular matchmaker in the MMR system. It has a weak ATPase Demeclocycline function, binds to DNA, interacts directly with MutS, MutH and UvrD, and is required for initiation as well as subsequent steps in MMR processes (Ban & Yang, 1998; Hall et al., 1998; Ban et al., 1999; Spampinato & Modrich, 2000). The deleted sequence that we identified in mutL is one of three tandem 6-bp

repeats, GCTGGC GCTGGC GCTGGC. Similar repeats were reported in Escherichia coli, although they were presented as G CTGGCG CTGGCG CTGGCG (Shaver & Sniegowski, 2003). The sequence (G)CTGGC GCTGGC GCTGGC C in Salmonella and (G) CTGGCG CTGGCG CTGGCG in E. coli both code for the amino acid sequence LALALA, which lies in a region of MutL that forms the lid of the ATP-binding pocket (Ban & Yang, 1998; Ban et al., 1999; Yang, 2000; Yang et al., 2000). In our case, the deletion of one of the 6-bp repeats will lead to one of the three LA sets missing in the ATP lid structure of MutL and may thus impair ATPase activity. As the repeat structure would facilitate deletion or duplication via slipped-strand mispairing (Streisinger et al., 1966; Levinson & Gutman, 1987), one can imagine that MMR may cease functioning when the 6-bp repeats of mutL decrease or increase one or more copies and resume functioning when the copy number again becomes three, both by ‘errors’ during replication.