Research Article: DNA Damage Repair and Bacterial Pathogens

Date Published: November 7, 2013

Publisher: Public Library of Science

Author(s): Darja Žgur-Bertok, Virginia Miller.

http://doi.org/10.1371/journal.ppat.1003711

Abstract

Partial Text

All species require DNA repair pathways to maintain the integrity of their genomes. Bacterial damage repair mechanisms have broader roles encompassing responses to stress, long-term colonization, as well as virulence. The SOS response regulates DNA repair and damage tolerance genes in many bacterial species. This article highlights the bacterial SOS response and its significance in bacterial adaptation and pathogenesis, as well as DNA damage responses provoked by bacterial pathogens in the mammalian host.

The SOS response is an inducible pathway governing DNA repair that was first described in Escherichia coli. Two key proteins govern the SOS response: LexA (a repressor) and RecA (an inducer). In the absence of DNA damage, a LexA dimer binds to SOS boxes, a 20 base pair consensus palindromic DNA sequence, repressing transcription of a regulon encompassing more than 50 genes, including lexA and recA. Upon DNA damage, RecA is activated (RecA*) by binding to single-stranded DNA (ssDNA) to form a nucleoprotein filament. RecA* stimulates self-cleavage of LexA, leading to derepression of SOS genes. In the absence of DNA damage, basal-level expression of lexA ensures downregulation of the system (Figure 1) [1].

Various exogenous and endogenous triggers provoke the SOS response. Exogenous triggers include UV irradiation, chemicals or oxidative compounds, acids, organic mutagens, some antibiotics (e.g., fluoroquinolones such as ciprofloxacin), trimethoprim, ß lactam, and physical stressors (such as high pressure) that provoke activity of the Mrr restriction endonuclease generating DNA double-strand breaks (DBSs) [2]. Moreover, in Vibrio cholerae additional non-genotoxic antibiotics have been shown to induce the SOS response, namely, aminoglycosides, tetracycline, and chloramphenicol [3]. Endogenous triggers are stalled replication forks, defects following recombination or chromosome segregation, as well as metabolic by-products. Reactive oxygen species (ROS), such as superoxide radical (O2−), hydrogen peroxide (H2O2), and the highly reactive hydroxyl radical (·OH), are generated continuously as by-products of aerobic metabolism. ROS damage DNA, RNA, proteins, and lipids. The targeting of DNA encompasses attacks of base and sugar moieties provoking single- and double-strand breaks, adducts of base and sugar groups, and cross-links to other molecules—all lesions that block DNA replication [4].

Whilst the SOS response was initially recognized as regulating DNA damage repair, its broader role is now well established. The SOS error-prone polymerases that enable translesion DNA synthesis also promote an elevated mutation rate that generates genetic diversity and adaptation, including the evolution of antibiotic resistance. Further, bacterial species produce a small subpopulation of transiently dormant persister cells that are tolerant of antimicrobials. Persisters play a key role in chronic bacterial infections. In E. coli, the SOS-controlled tisB gene, which encodes the toxin of the tisB-istR1 toxin-antitoxin system, is involved in persister formation. TisB is a small membrane-acting peptide that decreases the proton motive force and ATP levels, which induces dormancy by shutting down cell metabolism [7].

Almost all bacterial phyla harbor a lexA gene with characteristic SOS boxes [1]. Whilst the SOS response plays an important role in the lifestyle and virulence of a number of significant pathogens, nevertheless, not all pathogens possess an SOS response. Notable pathogens that lack an SOS response are: Campylobacter jejuni, Streptococcus pneumoniea, Streptococcus pyogenes, Legionella pneumophila, Helicobacter pylori, Neisseriae meningititis, and Neisseriae gonorherae. In S. pneumoniae, L. pneumophila, and H. pylori, antibiotics provoke the induction of competence for transformation; therefore, in these species competence might substitute for SOS [18]. Competence has been hypothesized to enable DNA uptake as a nutrient to serve as a template for DNA damage repair or for genetic exchange. Nevertheless, in these three species competence is not induced by the same antibiotics, which indicates a specific fine-tuning of the response. The correlation between a lack of SOS response and competence induction by antibiotics warrants examination among other naturally competent pathogens.

Whilst DNA damage repair systems play a significant role in survival and adaptation of bacterial pathogens, the latter does so by provoking chronic inflammation and/or production of genotoxins, which incite DNA damage and subsequent repair in host cells.

The bacterial SOS response regulates DNA repair and restart of stalled replication forks. Induction of the SOS response affects bacterial adaptation to stress, including antimicrobial tolerance, resistance, and virulence. Blocking SOS induction could be a means of preventing the evolution of bacterial resistance and of controlling significant pathogens. In turn, bacterial pathogens in host cells provoke DNA damage and DNA repair due to chronic inflammation and/or production of genotoxins.

 

Source:

http://doi.org/10.1371/journal.ppat.1003711