Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death.
Mol Microbiol
; 114(4): 641-652, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32634279
ABSTRACT
Of the ~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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistemas Toxina-Antitoxina
/
Mycobacterium tuberculosis
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article