Streptomyces coelicolor macrodomain hydrolase SCO6735 cleaves thymidine-linked ADP-ribosylation of DNA

Hloušek-Kasun, Andrea; Mikolčević, Petra; Rack, J.G.M.; Tromans-Coia, Callum; Schuller, M.; Jankevicius, Gytis; Matković, Marija; Bertoša, Branimir; Ahel, Ivan; Mikoč, Andreja

doi:10.1016/j.csbj.2022.08.002

Cited by 2 publications

(4 citation statements)

References 86 publications

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“…Similar reversal activity has been described for the macrodomain hydrolase SCO6735, known for its regulatory role in antibiotic production in S. coelicolor [ 102 ]. SCO6735 has been identified as a functional homologue of DarG as it neutralises DarT activity by hydrolysing the thymidine-linked DNA-ADP-ribosylation [ 119 ]. Structural studies have shown that SCO6735 has a notable structural similarity to T. aquaticus DarG and human TARG1, even though TARG1 and SCO6735 also de-MARylate protein targets while DarG does not [ 119 ].…”

Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

“…SCO6735 has been identified as a functional homologue of DarG as it neutralises DarT activity by hydrolysing the thymidine-linked DNA-ADP-ribosylation [ 119 ]. Structural studies have shown that SCO6735 has a notable structural similarity to T. aquaticus DarG and human TARG1, even though TARG1 and SCO6735 also de-MARylate protein targets while DarG does not [ 119 ]. The overall macrodomain fold in SCO6735 is conserved ( Figure 3 B); the superimposition of the SCO6735 crystal structure with TARG1 and DarG in complex with ADP-ribose revealed a putative active site confined by three loops.…”

Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

“…The mutation of Q85, located in an equivalent position to the catalytic lysine in DarG and TARG1 (K80 and K84, respectively), leads to a complete loss of activity. These observations suggest a diversification of catalytic reaction in this sub-class of macrodomain hydrolases, providing the rationale for the design of selective inhibitors or even agonists [ 119 ].…”

Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

“…Identities are indicated in light blue. ( B ) Structural comparison between DarG from T. aquaticus in complex with ADP-ribose (yellow line, PDB: 5M3E, [ 38 ]), human TARG1 in complex with ADP-ribose (blue line, PDB:4J5S, [ 55 ]) and SCO6735 (red line, PDB:5E3B, [ 119 ]). ( C ) DarG from T. aquaticus (cartoon) in complex with ADP-ribose (ball and stick).…”

Section: Figurementioning

confidence: 99%

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The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

2023

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The chemical modification of cellular macromolecules by the transfer of ADP-ribose unit(s), known as ADP-ribosylation, is an ancient homeostatic and stress response control system. Highly conserved across the evolution, ADP-ribosyltransferases and ADP-ribosylhydrolases control ADP-ribosylation signalling and cellular responses. In addition to proteins, both prokaryotic and eukaryotic transferases can covalently link ADP-ribosylation to different conformations of nucleic acids, thus highlighting the evolutionary conservation of archaic stress response mechanisms. Here, we report several structural and functional aspects of DNA ADP-ribosylation modification controlled by the prototype DarT and DarG pair, which show ADP-ribosyltransferase and hydrolase activity, respectively. DarT/DarG is a toxin–antitoxin system conserved in many bacterial pathogens, for example in Mycobacterium tuberculosis, which regulates two clinically important processes for human health, namely, growth control and the anti-phage response. The chemical modulation of the DarT/DarG system by selective inhibitors may thus represent an exciting strategy to tackle resistance to current antimicrobial therapies.

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Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

Section: The Dart/darg Adp-ribosylation-dependent Systemmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

2023

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Specificity of DNA ADP-Ribosylation Reversal by NADARs

Cihlova,

Lu,

Mikoč

et al. 2024

Toxins

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Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- and ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation and serve as antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, and viruses, their specificity and broader physiological roles remain poorly understood. Using phylogenetic and biochemical analyses, we further explore de-ADP-ribosylation activity and antitoxin functions of NADAR domains. We demonstrate that different subfamilies of NADAR proteins from representative E. coli strains and an E. coli-infecting phage retain biochemical activity while displaying specificity in providing protection from toxic guanine ADP-ribosylation in cells. Furthermore, we identify a myxobacterial enzyme within the YbiA subfamily that functions as an antitoxin for its associated DarT-unrelated ART toxin, which we termed YarT, thus presenting a hitherto uncharacterised ART-YbiA toxin–antitoxin pair. Our studies contribute to the burgeoning field of DNA ADP-ribosylation, supporting its physiological relevance within and beyond bacterial toxin–antitoxin systems. Notably, the specificity and confinement of NADARs to non-mammals infer their potential as highly specific targets for antimicrobial drugs with minimal off-target effects.

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Streptomyces coelicolor macrodomain hydrolase SCO6735 cleaves thymidine-linked ADP-ribosylation of DNA

Cited by 2 publications

References 86 publications

The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

Specificity of DNA ADP-Ribosylation Reversal by NADARs

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