New Facets in the Regulation of Gene Expression by ADP-Ribosylation and Poly(ADP-ribose) Polymerases

In 1963, Chambon et al. reported the detection of a nicotinamide mononucleotide-activated, DNA-dependent enzymatic activity in rat liver extracts that catalyzed the synthesis of a polyadenylic acid.1 The product of this reaction was later identified as poly(ADP-ribose) or PAR, a polymer of ADP-ribose (ADPR) monomers derived from the oxidized form of nicotinamide adenine dinucleotide (NAD+).2 These initial studies have led to half a century of research on the chemistry, enzymology, structure, function, biology, physiology, and pathology of ADPR, PAR, and their derivatives, as well as the enzymes that catalyze their synthesis and degradation, and the effector proteins that interact with or are posttranslationally modified by them. In this Review, we describe the biological chemistry of PAR and its associated enzymes, effector proteins, and targets, with a particular emphasis on their roles in gene regulation, from chromatin to RNA biology. 1.1. The PARP Family The synthesis of PAR from NAD+ is catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes belonging to the PARP family (EC 2.4.2.30), which contains at least 17 distinct proteins (Table 1).3 Not all PARP family members are enzymatically active, and some may function as mono(ADP-ribosyl)transferases rather than PARPs.4 As a consequence, a new nomenclature describing PARPs more accurately as ADP-ribosyltransferases (ARTs) has been proposed.5 The 17 PARP family members can be subdivided into four subfamilies based on their domain architectures (Table 1).3 These include: (1) DNA-dependent PARPs (PARP-1, PARP-2, and PARP-3), which are activated by discontinuous DNA structures (for PARPs 1 and 2, through their amino-terminal DNA binding domains) (Figure (Figure1);1); (2) tankyrases, including PARP5a (tankyrase-1) and PARP-5b (tankyrase-2), which contain large ankyrin domain repeats that mediate protein–protein interactions; (3) CCCH PARPs, including PARP-7 (tiPARP), PARP-12, PARP13.1, and PARP13.2, which contain Cys-Cys-Cys-His zinc fingers that bind to RNA, as well as WWE domains, which can exhibit PAR binding activity; and (4) macroPARPs, including PARP-9 (BAL1), PARP14 (BAL2, CoaSt6), and PARP-15 (BAL3), which contain macrodomain folds that can bind ADPR and derivatives. As these examples illustrate, nature through the course of evolution has modified the PARP catalytic domain and functionalized it with a variety of other protein domains to create a set of proteins with varied activities, subcellular locations, and functions. Figure 1 Structural and functional organization of nuclear DNA-dependent PARPs, as well as PARP-13. PARPs 1, 2, and 3 comprise a subset of nuclear PARPs whose catalytic activity is stimulated by discontinuous DNA structures. In the case of PARPs 1 and 2, this ...