Bacterial phenotypic heterogeneity in DNA repair and mutagenesis

Abstract

Genetically identical cells frequently exhibit striking heterogeneity in various phenotypic traits such as their morphology, growth rate, or gene expression. Such non-genetic diversity can help clonal bacterial populations overcome transient environmental challenges without compromising genome stability, while genetic change is required for long-term heritable adaptation. At the heart of the balance between genome stability and plasticity are the DNA repair pathways that shield DNA from lesions and reverse errors arising from the imperfect DNA replication machinery. In principle, phenotypic heterogeneity in the expression and activity of DNA repair pathways can modulate mutation rates in single cells and thus be a source of heritable genetic diversity, effectively reversing the genotype-to-phenotype dogma. Long-standing evidence for mutation rate heterogeneity comes from genetics experiments on cell populations, which are now complemented by direct measurements on individual living cells. These measurements are increasingly performed using fluorescence microscopy with a temporal and spatial resolution that enables localising, tracking, and counting proteins with single-molecule sensitivity. In this review, we discuss which molecular processes lead to phenotypic heterogeneity in DNA repair and consider the potential consequences on genome stability and dynamics in bacteria. We further inspect these concepts in the context of DNA damage and mutation induced by antibiotics.

Waddington’s Landscapes in the Bacterial World

“…Heterogeneous expression may be a common feature of DNA repair systems (Vincent and Uphoff, 2020). As a consequence, repair of DNA lesions by the adaptive response to DNA alkylation damage may be accompanied by an increase in the mutation rate in individual cells (Uphoff et al, 2016).…”

Transcription-coupled DNA repair underlies variation in persister awakening and the emergence of resistance

“…Importantly, subpopulations with different mutation rates were observed before and it was postulated to be a bet-hedging strategy (67, 68, 73). Our work links extended awakening lags with a higher mutation rate (Figure 6), shifting the balance between genome integrity and plasticity in time, which might be a strategy of the persister population to preserve genome integrity of the population if mutagenesis is not needed (74).…”

Genome-Wide Identification and Expression Analysis of SOS Response Genes in Salmonella enterica Serovar Typhimurium

“…Variation of mutation rates has been also observed in E. coli cells that undergo stochastic activation of the adaptive response to DNA alkylation damage [ 78 ]. Cell-to-cell heterogeneity may thus be a common feature of DNA repair systems [ 79 ]. Because of the relevance of DNA repair for survival and evolution, formation of bacterial cell variants may increase the adaptive capacity of the population under environmental threat [ 80 , 81 , 82 , 83 ].…”