Unravelling the poly(ADP-ribose) code: How the structural diversity of the post-translational modification poly(ADP-ribose) affects biochemical and biological processes

Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification (PTM), which is formed by poly(ADP-ribose) polymerases (PARPs). PARPs use NAD+ as a substrate to modify target proteins with the nucleic-acid-like biopolymer poly(ADP-ribose) (PAR), with variable branching frequencies and chain lengths. Covalent modification as well as non-covalent PAR binding regulate physico-chemical properties of hundreds of target proteins, thereby modifying their enzymatic activities, localization, and macromolecular interactions. Importantly, PARylation represents a fully reversible and highly dynamic PTM, because shortly after being synthesized, PAR is rapidly hydrolyzed by PAR-catabolizing enzymes. Thereby, PARylation acts as a key mediator and regulator of cellular stress response on multiple levels. Thus, it is involved in genome maintenance, chromatin remodeling, gene transcription, RNA metabolism, cell cycle control, cellular energy metabolism, inflammation and the regulation of cell death (see Figure). On the organismic level, this leads to pleiotropic functions of PARylation in physiology and pathophysiology, in particular, in processes related to cancer and aging. This has important translational implications: On the one hand, several pharmacological PARP inhibitors have been approved for the treatment of specific types of cancers, i.e., following the concept of synthetic lethality. On the other hand, molecules that increase levels of PARPs’ substrate NAD+ in vitro and in vivo, so-called NAD+ boosters, are being tested for therapeutic effects on age-related diseases in several organisms including humans.
In this talk, I will cover our recent investigations on how the structural diversity of poly(ADP-ribose) molecules with respect to chain lengths and branching frequencies affects biochemical and biological processes.