Abstract
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.
Introduction
ADP-ribosylation is a reversible post-translational modification (PTM) found in all three domains of life, as well as in several viruses.
It was identified in the 1970s as a key enzymatic activity required for cholera and diphtheria toxin pathogenesis. Since then, the understanding of ADP-ribosylation has increased, from bacteria to mammals. Today, it is mainly known in the scientific community for its key role in DNA damage repair [7,8,9,10] and for being the target of tailored cancer therapies.
However, the functions of ADP-ribosylation are also vital for controlling many additional physiological processes, such as transcription and translation, cell proliferation, and cell death along with stress and immune responses and many others.
The control of cell homeostasis in both prokaryotes and eukaryotes by ADP-ribosylation makes this a PTM of great interest in many fields of human health. […]
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