Adaptive mutation sequences reproduced by mismatch repair deficiency.

Abstract

Adaptive reversions of a lac frameshift mutation in Escherichia coli are -1 deletions in small mononucleotide repeats, whereas growth-dependent reversions are heterogeneous. The adaptive mutations resemble instability of simple repeats, which, in hereditary colon cancer, in yeast, and in E. coli occurs in the absence of mismatch repair. The postulate that mismatch repair is disabled transiently during adaptive mutation in E. coli is supported here by the demonstration that the growth-dependent mutation spectrum can be made indistinguishable from adaptive mutations by disallowing mismatch repair during growth. Physiologically induced mismatch repair deficiency could be an important mutagenic mechanism in cancers and in evolution.Adaptive mutations occur in the apparent absence of cell division, in cells exposed to a nonlethal selection (1-6), and have been detected only in genes whose function was selected (refs. 2, 4, .and 7, but see ref. 6). Thus, these mutations differ from spontaneous mutations in growing cells. In an experimental system that detects reversion of a + 1 frameshift mutation in an Escherichia coli lacI-lacZ fusion gene (2), the adaptive mutations are further distinguished from the growthdependent reversions by their molecular mechanism of formation and by their sequences. The adaptive reversions alone require genes of the E. coli RecBCD recombination system (8), implying that genetic recombination is part of the molecular mechanism by which they form. Also, the adaptive Lac' reversions are almost all single-base deletions in small mononucleotide repeats, whereas the growth-dependent Lac+ reversions include large and small insertions, deletions, and duplications and are not confined to simple repeats (9,10). This paper addresses the origin of the unusual sequence spectrum of the adaptive reversions of the lac +1 frameshift mutation.

Frameshift Intermediates in Homopolymer Runs Are Removed Efficiently by Yeast Mismatch Repair Proteins

“…Although we cannot eliminate a role for Msh2p in recognizing other types of Ϫ1 frameshift intermediates, there clearly is a strong preference for events in the longer mononucleotide runs. A similar bias has been reported for frameshift mutations in MMR-defective E. coli cells (26,41). An interesting issue that emerges concerns the targeted repair of an extrahelical base in a mononucleotide run versus an extrahelical base in noniterated sequences.…”

5-Methylcytosine is not a mutation hot spot in nondividing Escherichia coli

“…27). It has been suggested that DNA replication accompanied by a shortage of MutS and͞or MutL could account for the high rate of mutation observed in some starved bacteria (28)(29)(30). MutS protein appears to be very unstable in bacteria grown to maximum density in an enriched mineral salts plus glucose medium (31).…”

The SOS response regulates adaptive mutation

“…65). Mismatch repair activity is diminished transiently (28,34,52) in the stressed, mutating cells due to a transient limitation of MutL (31,66). This allows the errors to be fixed as mutations.…”

“…18 and 19) that requires homologous recombination proteins RecA, RecBC, and RuvABC (22,26,27). The adaptive mutations occur in a hypermutable subpopulation of the starved cells (28)(29)(30) during a transient period of limiting mismatch-repair activity (31) and possess a unique sequence spectrum of Ϫ1 deletions in mononucleotide repeats (32,33) identical to that of mismatch repair defective cells (34).…”