Type II toxin-antitoxin systems as stress-responsive survival circuits in archaea and bacteria

Abstract

Simple early lifeforms with relatively small genomes were evolved with certain genetic circuitry to better their stress-response mechanism which significantly enhances their survival during stress, hypothetically. In this review, we conducted a comprehensive investigation to identify survival-focused genetic circuitry in microorganisms, focusing on type II toxin-antitoxin (TA) systems, particularly sought after due to their ubiquitousness in nature, composed of two functionally coordinated genes: one that transiently inhibits reproduction during stress and another that represses this inhibition under normal conditions, while simultaneously promoting DNA repair under stress. Our comprehensive analysis of 22 type II TA systems reveals diverse roles, including dormancy induction, biofilm formation, pathogenicity and DNA repair. While canonical modules such as HigAB and RelBE are well-characterized, others like ParDE, Kid-Kis, and YafO-YafN remain understudied in the context of dormancy or biofilm involvement. Additionally, systems such as DarT-DarG, YafQ-DinJ and CcdB-CcdA have been implicated in DNA repair pathways, suggesting broader functional repertoires beyond growth inhibition. Phylogenetic analyses further reveal that TA systems such as VapC-VapB and MazF-MazE are widely distributed among bacteria, archaea, and cyanobacteria, including lineages thriving in extreme environments like deep-sea hydrothermal vents, which are considered potential sites for the emergence of early life. The presence of TA loci in ancient microorganisms like Methanocaldococcus jannaschii and Microcystis aeruginosa hints at their ancient origin and possible role in microbial survival on early Earth. This review synthesizes current knowledge on type II TA systems as stress-responsive survival circuits and highlights their significance in microbial ecology, evolution, and adaptation.