The expanding field of poly(ADP-ribosyl)ation reactions. 'Protein Modifications: Beyond the Usual Suspects' Review Series

Abstract

Poly(ADP-ribosyl)ation is a post-translational modification of proteins that is mediated by poly(ADP-ribose) polymerases (PARPs). Although the existence and nature of the nucleic acid-like molecule poly(ADP-ribose) (PAR) has been known for 40 years, understanding its biological functions--originally thought to be only the regulation of chromatin superstructure when DNA is broken--is still the subject of intense research. Here, we review the mechanisms controlling the biosynthesis of this complex macromolecule and some of its main biological functions, with an emphasis on the most recent advances and hypotheses that have developed in this rapidly growing field.

Figure 1

Metabolism of poly(ADP-ribose). PARPs hydrolyse NAD⁺ and catalyse the successive addition of ADP-ribose units mainly to glutamate residues of either acceptor proteins (heteromodification) or themselves (automodification). PAR is heterogeneous in size and complexity, as indicated by the x, y and z labels that represent values from 0 to >200. PARG and ARH3 can both hydrolyse PAR at the indicated positions; activators and outcomes of PAR synthesis are indicated. Ade, adenine; ARH3, ADP-ribosyl hydrolase-3; Nam, nicotinamide; PAR, poly(ADP-ribose); PARG, poly(ADP-ribose) glycohydrolase; PARP, poly(ADP-ribose) polymerase; Rib, ribose.

Figure 2

Domain architecture of human poly(ADP-ribose) polymerase family members. Within each putative PARP domain, the region that is homologous to residues 859–908 of PARP1—the PARP signature—is indicated by a darker colour. BRCT, SAM, UIM, MVP-BD, VWA and ANK are protein-interaction modules. ANK, ankyrin; BRCT, BRCA1-carboxy-terminus; HPS, homopolymeric runs of His, Pro and Ser; macro, domain involved in ADP-ribose and poly(ADP-ribose) binding; MVP-BD, MVP-binding; NES, nuclear export signal; N(o)LS, nuclear (nucleolar) localization signal; PARP, poly(ADP-ribose) polymerase; PARP_Reg, putative regulatory domain; RRM, RNA-binding motif; SAM, sterile α-motif; TiPARP, 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly(ADP-ribose) polymerase; UIM, ubiquitin-interacting motif; VIT, vault inter-α-trypsin; vPARP, vault poly(ADP-ribose) polymerase; vWA, von Willebrand factor type A; WGR, conserved W, G and R residues; WWE, conserved W, W and E residues; ZnF, DNA or RNA binding zinc fingers (except PARP1 ZnFIII, which coordinates DNA-dependent enzyme activation).

From left: Heng-Kuan Wong, Valérie Schreiber, Antoinette Hakmé & Françoise Dantzer