MOLECULAR MECHANISM OF ADAPTIVE MUTATION IN E.COLI

Baylor College Of Medicine, Houston TX

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Abstract

DESCRIPTION (provided by the applicant): Spontaneous mutations drive evolution, and are also important in many medical contexts including the original and progression of some cancers, development of resistance to chemotherapeutic and antibiotic drugs, and evasion of the immune response by pathogens. In the past decade, understanding of spontaneous mutation h; expanded with the discovery that some mutational processes are not purely random, but can be induced b environmental conditions favoring genetic change. These "adaptive" (or stationary-phase) mutations occurring in slowly-growing or non-growing cells, only after the cells are exposed to a growth-limiting environment, and cz confer a growth advantage in that environment. Little is known about the mechanisms of stationary-phase mutation in most of the assays in which they have been reported in bacteria and yeast. However, in our system, reversion of a lacframe-shift mutation in Escherichia coli, aspects of the molecular mechanism is becoming apparent, and indicate a novel mutagenic route. The mechanism involves DNA double-strand break homologous recombination, DNA synthesis and polymerase errors, a transient depression of post-synthesis mismatch repair capacity, and the SOS DNA damage response. The mutations are not directed in a Lamarckia manner to lac gene, and are not specific to the episomal replicon that carries lac. Some, or all of the cells thz acquire a Lac+ adaptive mutation have experienced transient hyper-mutability, affecting genes throughout their genomes. This project is aimed at providing a complete description of the molecular mechanism of stationary phase mutation in the lacsystem. Understanding the molecular mechanism will provide a valuable new mod about for mutation in non-dividing and slowly growing cells. This model may apply to many systems previously assumed to follow the rules of Luria/Delbruck growth-dependent mutation, occurring randomly before selective environments are encountered.