Title | Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Zaveri A, Wang R, Botella L, Sharma R, Zhu L, Wallach JB, Song N, Jansen RS, Rhee KY, Ehrt, Sabine, Schnappinger D |
Journal | Mol Microbiol |
Volume | 114 |
Issue | 4 |
Pagination | 641-652 |
Date Published | 2020 10 |
ISSN | 1365-2958 |
Keywords | Animals, Antitoxins, Bacterial Proteins, Bacterial Toxins, Cell Death, DNA, Female, Mice, Mice, Inbred C57BL, Microbial Viability, Mycobacterium tuberculosis, Toxin-Antitoxin Systems |
Abstract | Of theĀ ~80 putative toxin-antitoxin (TA) modules encoded by the bacterial pathogen Mycobacterium tuberculosis (Mtb), three contain antitoxins essential for bacterial viability. One of these, Rv0060 (DNA ADP-ribosyl glycohydrolase, DarGMtb ), functions along with its cognate toxin Rv0059 (DNA ADP-ribosyl transferase, DarTMtb ), to mediate reversible DNA ADP-ribosylation (Jankevicius et al., 2016). We demonstrate that DarTMtb -DarGMtb form a functional TA pair and essentiality of darGMtb is dependent on the presence of darTMtb , but simultaneous deletion of both darTMtb -darGMtb does not alter viability of Mtb in vitro or in mice. The antitoxin, DarGMtb , forms a cytosolic complex with DNA-repair proteins that assembles independently of either DarTMtb or interaction with DNA. Depletion of DarGMtb alone is bactericidal, a phenotype that is rescued by expression of an orthologous antitoxin, DarGTaq , from Thermus aquaticus. Partial depletion of DarGMtb triggers a DNA-damage response and sensitizes Mtb to drugs targeting DNA metabolism and respiration. Induction of the DNA-damage response is essential for Mtb to survive partial DarGMtb -depletion and leads to a hypermutable phenotype. |
DOI | 10.1111/mmi.14571 |
Alternate Journal | Mol Microbiol |
PubMed ID | 32634279 |
PubMed Central ID | PMC7689832 |
Grant List | U19 AI107774 / AI / NIAID NIH HHS / United States U19 AI111143 / AI / NIAID NIH HHS / United States |