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Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death.
Molecular Microbiology ( IF 2.6 ) Pub Date : 2020-07-07 , DOI: 10.1111/mmi.14571 Anisha Zaveri 1 , Ruojun Wang 1 , Laure Botella 1 , Ritu Sharma 1 , Linnan Zhu 1 , Joshua B Wallach 1 , Naomi Song 1 , Robert S Jansen 2 , Kyu Y Rhee 2 , Sabine Ehrt 1 , Dirk Schnappinger 1
Molecular Microbiology ( IF 2.6 ) Pub Date : 2020-07-07 , DOI: 10.1111/mmi.14571 Anisha Zaveri 1 , Ruojun Wang 1 , Laure Botella 1 , Ritu Sharma 1 , Linnan Zhu 1 , Joshua B Wallach 1 , Naomi Song 1 , Robert S Jansen 2 , Kyu Y Rhee 2 , Sabine Ehrt 1 , Dirk Schnappinger 1
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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.
中文翻译：
结核分枝杆菌中DarG抗毒素的耗尽会触发DNA损伤反应并导致细胞死亡。
由细菌病原体结核分枝杆菌（Mtb）编码的约80种假定毒素-抗毒素（TA）模块中，三种包含对细菌生存力必不可少的抗毒素。其中之一是Rv0060（DNA ADP-核糖基糖基水解酶，DarG Mtb），与它的同源毒素Rv0059（DNA ADP-核糖基转移酶，DarT Mtb）一起起作用，以介导可逆的DNA ADP-核糖基化（Jankevicius等，2016）。我们表明，镖的Mtb -DarG Mtb的形成功能TA对和的必要性DARG Mtb的是依赖于存在镖的Mtb两者，但同时缺失镖Mtb- darG Mtb不会改变Mtb在体外或小鼠中的活力。抗毒素DarG Mtb与DNA修复蛋白形成胞质复合物，其组装独立于DarT Mtb或与DNA相互作用。单独消耗DarG Mtb具有杀菌作用，该表型可通过表达水生栖热菌（ Thermus aquaticus）的直系同源抗毒素DarG Taq来挽救。DarG Mtb的部分消耗会触发DNA损伤反应，并使Mtb对靶向DNA代谢和呼吸的药物敏感。DNA损伤反应的诱导对于Mtb在部分DarG中存活至关重要Mtb耗尽并导致超变表型。
更新日期：2020-07-07
中文翻译：
结核分枝杆菌中DarG抗毒素的耗尽会触发DNA损伤反应并导致细胞死亡。
由细菌病原体结核分枝杆菌（Mtb）编码的约80种假定毒素-抗毒素（TA）模块中，三种包含对细菌生存力必不可少的抗毒素。其中之一是Rv0060（DNA ADP-核糖基糖基水解酶，DarG Mtb），与它的同源毒素Rv0059（DNA ADP-核糖基转移酶，DarT Mtb）一起起作用，以介导可逆的DNA ADP-核糖基化（Jankevicius等，2016）。我们表明，镖的Mtb -DarG Mtb的形成功能TA对和的必要性DARG Mtb的是依赖于存在镖的Mtb两者，但同时缺失镖Mtb- darG Mtb不会改变Mtb在体外或小鼠中的活力。抗毒素DarG Mtb与DNA修复蛋白形成胞质复合物，其组装独立于DarT Mtb或与DNA相互作用。单独消耗DarG Mtb具有杀菌作用，该表型可通过表达水生栖热菌（ Thermus aquaticus）的直系同源抗毒素DarG Taq来挽救。DarG Mtb的部分消耗会触发DNA损伤反应，并使Mtb对靶向DNA代谢和呼吸的药物敏感。DNA损伤反应的诱导对于Mtb在部分DarG中存活至关重要Mtb耗尽并导致超变表型。
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