MOLECULAR MECHANISM OF ADAPTIVE MUTATION IN E COLI

Baylor College Of Medicine, Houston TX

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Abstract

DESCRIPTION: (adapted from investigator's abstract) "Adaptive " mutations occur in stationary cell populations, only after the cells are exposed to selection for the mutation, and, previously, had been found only in genes whose functions were selected. Their discovery challenged established ideas about the mechanisms of mutation and evolution. In one system, reversion of a lac frameshift mutation in E. coli, aspects of the molecular mechanism are becoming apparent, and indicate a novel mutagenic route involving DNA double strand breaks, homologous recombination, DNA synthesis with polymerase errors, and depression of post-synthesis mismatch repair at the protein level. This mechanism is general to all replicons in the cell, not directed to the lac gene in a Lamarckian manner, and occurs in a hypermutable subpopulation of the cells exposed to the selection. This proposal is aimed at providing a complete description of the molecular mechanism of the recombination dependent adaptive mutation in this system, and defining the generality of this mechanism elsewhere. Understanding the molecular mechanism will provide a valuable new model for mutagenesis in non-dividing and slowly growing cells. This model might apply to mutagenesis in the origins of some cancers and genetic diseases, evolution of drug resistance in tumors and pathogenic bacteria, and many other systems previously assumed to follow the rules of Luria/Delbruck growth-dependent mutation.