Physiology of ADP-ribosylation
Article first published online: 12 JUL 2013
© 2013 FEBS
Volume 280, Issue 15, page 3483, August 2013
How to Cite
Koch-Nolte, F. and Ziegler, M. (2013), Physiology of ADP-ribosylation. FEBS Journal, 280: 3483. doi: 10.1111/febs.12389
- Issue published online: 17 JUL 2013
- Article first published online: 12 JUL 2013
- Accepted manuscript online: 16 JUN 2013 06:23AM EST
ADP-ribosylation of proteins is emerging as a very versatile post-translational modification in various signalling pathways. In the cytosol of mammalian cells, this post-translational modification is mediated by enzymes with a diphtheria toxin-homology ADP-ribosyltransferase domain: the ARTD-family. Poly(ADP-ribosyl)ation, with the massive charge accumulation that it confers, can break up chromatin structure by interfering with protein–DNA interactions, as well as alter the surface properties of substrate proteins. Mono-ADP-ribosylation can alter the chemistry of specific protein side chains, provide a handle for the binding of a specific recognition or recruiting domain, or be a destruction mark on a protein substrate. In conjunction with these principles, various new therapeutic opportunities are emerging to be explored and new functional aspects are being revealed. In addition, novel tools are being developed that exploit the well-established inhibition of ARTD1, particularly in cancer therapeutics development.
Recently, at a Special Interest Symposium held within the frame of the EMBO2012 meeting, European researchers met to disseminate their latest results on this theme. Two series of minireviews represent a cross-section through these studies: this series focuses on the physiological aspects of ADP-ribosylation, whereas the companion series places special emphasis on aspects of drug target identification and pharmacology [Schuler H & Ziegler M (2013) FEBS J 280, 3542].
In the first minireview of this series, Francoise Dantzer and Raffaella Santoro describe the role of ARTD1 and ARTD2 in the establishment and inheritance of heterochromatic structures. Similar to other tightly regulated post-translational modifications, poly(ADP-ribosyl)ation employs writers, erasers and readers conferring regulatory functions. The minireview by Eva Barkauskaite, Gytis Jankevicius, Andreas G. Ladurner, Ivan Ahel and Gyula Timinszky summarizes the protein modules recognizing poly(ADP-ribose) and discusses the new developments on the reversibility of poly(ADP-ribosyl)ation.
Mono-ADP-ribosylation has also emerged as an important regulatory mechanism. A classic example is the regulation of nitrogen fixation in proteobacteria, a biochemical process by which atmospheric nitrogen is made available to the biosphere. This energetically costly pathway is tightly regulated by reversible ADP-ribosylation of the key enzyme: dinitrogenase reductase. Stefan Nordlund and Martin Högbom review the current biochemical and structural knowledge of this central regulatory reaction. Over recent years, tremendous progress has been made regarding the mechanisms and functions of endogenous mono-ADP-ribosylation in mammalian cells. The minireview by Karla Feijs, Patricia Verheugd and Bernhard Lüscher discusses the newly-identified roles of intracellular mono-ADP-ribosyltransfereases, as well as the recently discovered macrodomain-containing hydrolases, which reverse this protein modification.
Mitochondria are organelles that carry out important functions in almost all eukaryotic cells. Mitochondrial NAD+-consuming ADP-ribose transfer reactions have been described and are presented in the minireview by Christian Dölle, Johannes Rack and Mathias Ziegler. They highlight the generation and maintenance of the mitochondrial NAD+ pool, the major NAD+-dependent reactions occurring within mitochondria, and discuss the metabolic fates of the NAD+ degradation products: nicotinamide and ADP-ribose.