4.7 Article

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

期刊

出版社

ELSEVIER
DOI: 10.1016/j.csbj.2022.08.002

关键词

ADP-ribosylation; DNA ADP-ribosylation; Macrodomain; Streptomyces; SCO6735

资金

  1. Croatian Science Foundation [IP-2016-06-4242]
  2. Horizon 2020 Widening Fellowship (STREPUNLOCKED) [867468]
  3. Wellcome Trust [101794, 210634]
  4. Biotechnology and Biological Sciences Research Council [BB/R007195/1]
  5. Cancer Research United Kingdom [C35050/A22284]

向作者/读者索取更多资源

ADP-ribosylation is an important covalent modification that plays critical roles in various biological processes. The toxin/antitoxin pair DarT/DarG has been discovered, where DarT modifies DNA and DarG reverses this modification. The homologue SCO6735 is highly conserved and associated with antibiotic production in bacteria, and it can also reverse the ADP-ribosylation catalyzed by DarT.
ADP-ribosylation is an ancient, highly conserved, and reversible covalent modification critical for a vari-ety of endogenous processes in both prokaryotes and eukaryotes. ADP-ribosylation targets proteins, nucleic acids, and small molecules (including antibiotics). ADP-ribosylation signalling involves enzymes that add ADP-ribose to the target molecule, the (ADP-ribosyl)transferases; and those that remove it, the (ADP-ribosyl)hydrolases. Recently, the toxin/antitoxin pair DarT/DarG composed of a DNA ADP-ribosylating toxin, DarT, and (ADP-ribosyl)hydrolase antitoxin, DarG, was described. DarT modifies thy-midine in single-stranded DNA in a sequence-specific manner while DarG reverses this modification, thereby rescuing cells from DarT toxicity. We studied the DarG homologue SCO6735 which is highly con-served in all Streptomyces species and known to be associated with antibiotic production in the bacterium S. coelicolor. SCO6735 shares a high structural similarity with the bacterial DarG and human TARG1. Like DarG and TARG1, SCO6735 can also readily reverse thymidine-linked ADP-ribosylation catalysed by DarT in vitro and in cells. SCO6735 active site analysis including molecular dynamic simulations of its complex with ADP-ribosylated thymidine suggests a novel catalytic mechanism of DNA-(ADP-ribose) hydrolysis. Moreover, a comparison of SCO6735 structure with ALC1-like homologues revealed an evolutionarily conserved feature characteristic for this subclass of macrodomain hydrolases.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

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