Readers of poly(ADP-ribose): designed to be fit for purpose

Abstract

Post-translational modifications (PTMs) regulate many aspects of protein function and are indispensable for the spatio-temporal regulation of cellular processes. The proteome-wide identification of PTM targets has made significant progress in recent years, as has the characterization of their writers, readers, modifiers and erasers. One of the most elusive PTMs is poly(ADP-ribosyl)ation (PARylation), a nucleic acid-like PTM involved in chromatin dynamics, genome stability maintenance, transcription, cell metabolism and development. In this article, we provide an overview on our current understanding of the writers of this modification and their targets, as well as the enzymes that degrade and thereby modify and erase poly(ADP-ribose) (PAR). Since many cellular functions of PARylation are exerted through dynamic interactions of PAR-binding proteins with PAR, we discuss the readers of this modification and provide a synthesis of recent findings, which suggest that multiple structurally highly diverse reader modules, ranging from completely folded PAR-binding domains to intrinsically disordered sequence stretches, evolved as PAR effectors to carry out specific cellular functions.

Figure 1.

Readers of poly(ADP-ribose). PAR polymerases use NAD⁺ to generate highly anionic linear and branched (not shown) PAR chains of different size and branching complexity. Besides the classical, well-characterized PAR reader modules WWE, PBZ, PBM, and macrodomains (top) also newly emerging PAR reader modules such as FHA, OB-fold, PIN domain, RRM, SR and KR repeats, RGG repeats and BRCT (bottom) appear as PAR readers and effectors. Multi-branched arrows indicate that the exact binding sites have not been defined.

Figure 2.

PAR-seeded liquid demixing. PAR chains assemble hundreds of proteins, including many intrinsically disordered, low complexity domain-containing proteins, at sites of PAR formation, which collectively re-shape the local environment. This can lead to dynamic compartmentalization by liquid demixing, indicating that PAR can function as a general organizer of the soluble intracellular space.