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Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death.

TitleDepletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death.
Publication TypeJournal Article
Year of Publication2020
AuthorsZaveri A, Wang R, Botella L, Sharma R, Zhu L, Wallach JB, Song N, Jansen RS, Rhee KY, Ehrt S, Schnappinger D
JournalMol Microbiol
Date Published2020 Jul 07
ISSN1365-2958
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.

DOI10.1111/mmi.14571
Alternate JournalMol Microbiol
PubMed ID32634279
Grant ListU19 AI111143 / AI / NIAID NIH HHS / United States
U19 AI111143 / GF / NIH HHS / United States
U19 A107774 / GF / NIH HHS / United States

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