SUMMARY Since poly-ADP ribose was discovered over 40 years ago, there has been significant progress in research into the biology of mono- and poly-ADP-ribosylation reactions. During the last decade, it became clear that ADP-ribosylation reactions play important roles in a wide range of physiological and pathophysiological processes, including inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. ADP-ribosylation reactions are phylogenetically ancient and can be classified into four major groups: mono-ADP-ribosylation, poly-ADP-ribosylation, ADP-ribose cyclization, and formation of O-acetyl-ADP-ribose. In the human genome, more than 30 different genes coding for enzymes associated with distinct ADP-ribosylation activities have been identified. This review highlights the recent advances in the rapidly growing field of nuclear mono-ADP-ribosylation and poly-ADP-ribosylation reactions and the distinct ADP-ribosylating enzyme families involved in these processes, including the proposed family of novel poly-ADP-ribose polymerase-like mono-ADP-ribose transferases and the potential mono-ADP-ribosylation activities of the sirtuin family of NAD+-dependent histone deacetylases. A special focus is placed on the known roles of distinct mono- and poly-ADP-ribosylation reactions in physiological processes, such as mitosis, cellular differentiation and proliferation, telomere dynamics, and aging, as well as “programmed necrosis” (i.e., high-mobility-group protein B1 release) and apoptosis (i.e., apoptosis-inducing factor shuttling). The proposed molecular mechanisms involved in these processes, such as signaling, chromatin modification (i.e., “histone code”), and remodeling of chromatin structure (i.e., DNA damage response, transcriptional regulation, and insulator function), are described. A potential cross talk between nuclear ADP-ribosylation processes and other NAD+-dependent pathways is discussed.

Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor B (NF-B) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders. We recently presented evidence that PARP-1 can act as a promoter-specific coactivator of NF-B in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-B (p65 and p50) and synergistically coactivates NF-B-dependent transcription. Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation. Furthermore, acetylation of PARP-1 at these residues is required for the interaction of PARP-1 with p50 and synergistic coactivation of NF-B by p300 and the Mediator complex in response to inflammatory stimuli. PARP-1 physically interacts with the Mediator. Interestingly, PARP-1 interacts in vivo with histone deacetylases (HDACs) 1-3 but not with HDACs 4 -6 and might be deacetylated in vivo by HDACs 1-3. Thus, acetylation of PARP-1 by p300/CREB-binding protein plays an important regulatory role in NF-B-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.Nuclear factor B (NF-B) is a widely expressed transcription factor of particular importance to the regulation of cells of the immune system (1). NF-B encompasses a family of inducible transcription factors including RelA/p65, RelB, c-Rel, p50, and p52 (1). These proteins share a conserved 300-amino acid region within their amino termini, designated Rel-homology domain (RHD). This domain is responsible for dimerization, nuclear translocation, DNA binding, and interaction with heterologous transcription factors (1). NF-B is composed of homo-or heterodimers with a range of DNA binding and activation potentials. The most abundant and best-studied form of NF-B in cells is a heterodimer consisting of the two subunits, p50 (NF-B1) and p65 (RelA). NF-B plays a key role in the regulation of many genes involved in mammalian immune and inflammatory responses, apoptosis, cell proliferation, and differentiation (1, 2). NF-B has additionally been associated with neurodegenerative processes and cancer (3, 4). In unstimulated cells, NF-B is sequestered in the cytoplasm as an inactive transcription factor complex by its physical association with one of several inhibitors of NF-B (IBs) 2 (5). Treatment of cells with extracellular stimuli including cytokines, bacterial lipopolysaccharides (LPS), phorbol esters, or potent oxidants leads to rapid phosphorylation of IB␣, which results in ubiquitination of IB␣ and subsequent degradation by the 26 S proteasome (4, 5). Dissociation of NF-B unmasks the nuclear localization sequences of p65 and p50 subunits, which leads to nuclear translocation and binding of NF-B to specific B consensus sequences in the chromatin and activation of specific subsets of genes (3).NF-B-dependent gene expression requires growing families of transcriptional coactivators (6, 7). The two key coactivators of NF-B, histone acetyltransferases p300 and its homo...

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Background: The enzymes responsible for the synthesis of poly-ADP-ribose are named poly-ADP-ribose polymerases (PARP). PARP-2 is a nuclear protein, which regulates a variety of cellular functions that are mainly controlled by protein-protein interactions. A previously described nonconventional bipartite nuclear localization sequence (NLS) lies in the amino-terminal DNA binding domain of PARP-2 between amino acids 1-69; however, this targeting sequence has not been experimentally examined or validated.