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 S, Schnappinger D |
Journal | Mol Microbiol |
Date Published | 2020 Jul 07 |
ISSN | 1365-2958 |
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, DarG ), functions along with its cognate toxin Rv0059 (DNA ADP-ribosyl transferase, DarT ), to mediate reversible DNA ADP-ribosylation (Jankevicius et al., 2016). We demonstrate that DarT -DarG form a functional TA pair and essentiality of darG is dependent on the presence of darT , but simultaneous deletion of both darT -darG does not alter viability of Mtb in vitro or in mice. The antitoxin, DarG , forms a cytosolic complex with DNA-repair proteins that assembles independently of either DarT or interaction with DNA. Depletion of DarG alone is bactericidal, a phenotype that is rescued by expression of an orthologous antitoxin, DarG , from Thermus aquaticus. Partial depletion of DarG 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 DarG -depletion and leads to a hypermutable phenotype. |
DOI | 10.1111/mmi.14571 |
Alternate Journal | Mol Microbiol |
PubMed ID | 32634279 |
Grant List | U19 AI111143 / AI / NIAID NIH HHS / United States U19 AI111143 / GF / NIH HHS / United States U19 A107774 / GF / NIH HHS / United States |
Submitted by jom4013 on December 3, 2020 - 2:05pm