Kinetic models reveal the in vivo mechanisms of mutagenesis in microbes and man

Abstract

This review summarizes the evidence indicating that mutagenic mechanisms in vivo are essentially the same in all living cells. Unique metabolic reactions to a particular environmental stress apparently target specific genes for increased rates of transcription and mutation, resulting in higher mutation rates for those genes most likely to solve the problem. Kinetic models which have demonstrated predictive value are described and are shown to simulate mutagenesis in vivo in E. coli, the p53 tumor suppressor gene, and somatic hypermutation. In all three models, direct correlations are seen between mutation frequencies and transcription rates. G and C nucleosides in single-stranded DNA (ssDNA) are intrinsically mutable, and G and C silent mutations in p53 and in VH framework regions provide compelling evidence for intrinsic mechanisms of mutability, since mutation outcomes are neutral and are not selected. During transcription, the availability of unpaired bases in the ssDNA of secondary structures is rate-limiting for, and determines the frequency of mutations in vivo. In vitro analyses also verify the conclusion that intrinsically mutable bases are in fact located in ssDNA loops of predicted secondary structures.

Mutation Rate Heterogeneity Increases Odds of Survival in Unpredictable Environments

“…Support for the second hypothesis comes from the observation that there is positive correlation between high gene expression under stressful conditions and increased gene variability (Feugeas et al, 2016). Mutagenesis of genes highly expressed during stress may result from the exposure of the single-strand DNA that is intrinsically mutable (Wright et al, 2013) and from the formation of R-loops (Wimberly et al, 2013). Observed downregulation of transcription-coupled repair is expected to increase both events.…”

The Immune System and Responses to Cancer: Coordinated Evolution

“…Examples are the microorganisms that rapidly expand and produce outbreaks of disease in humans, animals (from insects to mammals), and, plants, sometimes with transmission across species. Rapid, immediate 'revolutionary' adaptive change is advantageous to keep the immune system ahead of microbial mutation, virulence and growth 37 . To oppose mutated, infected and otherwise aberrant cells, the immune system has a number of adaptive and protective mechanisms.…”