Regulation of Chromatin Structure and Gene Activity by Poly(ADP-Ribose) Polymerases

doi:10.1016/S0070-2153(03)01007-X

Current Topics in Developmental Biology

Volume 56, 2003, Pages 55-83

https://doi.org/10.1016/S0070-2153(03)01007-X Get rights and content

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear protein that plays an important role in repairing DNA and responding to infection. Here we review recent evidence that PARP1 and related proteins also carry out crucial functions regulating genes during normal development. Genetic studies in mammals and Drosophila have implied that PARPs mediate rapid responses to environmental stimuli, including infection, stress, hormones, and growth signals. In addition, these polymerases may control fundamental processes that differentially mold and remodel chromatin within the many cell types of a developing embryo. We discuss a unified mechanism of PARP action during DNA repair, gene transcription, and chromatin modulation.

Introduction

The first evidence that cells contain a polymerase that synthesizes long polymers of poly(ADP-ribose) (pADPr) in vivo from NAD was reported by Chambon et al. (1963). A variety of nuclear proteins including histones, RNA polymerase, transcription factors, and poly(ADP-ribose) polymerase (PARP) itself are covalently modified by this activity, which was found to increase more than 100-fold in response to genotoxic stress. During most of the ensuing decades, research focused largely on the roles played by PARP (and the enzymes pADPr glycohydrolase [PARG] and pADPr lyase that degrade ADP-ribose polymers) in response to DNA damage and related phenomena (reviewed in D'Amours 1999, de Murcia 2000, Ziegler 2001). Genetic studies (Shieh et al., 1998) and whole genome sequencing revealed that virtually all metazoan organisms contain multiple genes encoding PARP-related proteins. These include proteins such as PARP1, PARP2, PARP3, tankyrase, vault PARP (vPARP) (mammals), and PARP-e (Drosophila).

With the discovery of multiple PARPs, awareness has grown that the residual PARP activity in undamaged cells does not simply represent background repair processes but rather that poly(ADP-ribose) modifications play important roles in telomere maintenance (Smith and de Lange, 2000), cell cycle checkpoints (see Pleschke et al., 2000), apoptosis (reviewed in Chiarugi and Moskowitz, 2002), transcription (see de Murcia and Shall, 2000), and even in certain cytoplasmic events (Arnold 2002, Kickhoefer 1999, Mossink 2002). Genetic studies of PARP-deficient mice (Wang et al., 1997) and Drosophila (Tulin 2003, Tulin 2002; see Pirrotta, 2003) have greatly increased our understanding of these non-canonical PARP functions. Today, our view of the PARP family has reached a turning point; it is becoming clear that these abundant and ubiquitous proteins regulate fundamental aspects of chromosome and gene activity. In this review, we focus on how PARP functions to mediate chromatin structure and transcription. We discuss a unified mechanism for these roles and for the proposed action of PARP during DNA repair. First, however, we briefly review some basic information about PARP genes and proteins.

Section snippets

Poly(ADP-Ribose) Polymer Metabolism

The basic enzymatic reactions catalyzed by PARP involve transferring ADP-ribose from NAD to either a protein acceptor or to an existing ADP-ribose chain (Fig. 1). One of the most remarkable aspects of PARP from a biochemical perspective is that it is capable of three distinct activities, an unprecedented flexibility for a polymerase. The target is most commonly the COOH residue of a glutamic acid (Glu), but modification of other amino acids may occasionally occur. The first reaction is chain

Mechanism of Action

Previous studies have documented that PARP modulates multiple aspects of chromatin structure, including DNA repair (see de Murcia and Shall, 2000), telomere elongation (Smith and de Lange, 2000), centromere activity (Saxena et al., 2002a), and the availability of nuclear matrix attachment sites (Galande, 2002). In two of these cases, mechanisms were proposed in which PARP inactivated DNA-bound inhibitors by poly(ADP-ribose) modification (Fig. 4). Thus, following DNA damage, PARP1 becomes

Poly(ADP-Ribose) Polymerase and Transcription

It has been well established that PARP can bind to a variety of transcription factors, including NF-κB (Hassa and Hottiger, 2002), YY1 (Oei 2001, Oei 1997), Oct-1 (Oei et al., 1998), and AP-2 (Kannan et al., 1999), whereas other factors are targets of its enzymatic activity, including p53 (Wesierska-Gadek and Schmid, 2001) and fos (Amstad et al., 1992). Furthermore, evidence has been presented, some contradictory, that PARP plays a role in the induction or repression of target genes as a result

Multiple Routes to Poly(ADP-Ribose) Polymerase Activation

Based on the evidence, activated PARP1 plays important roles in gene transcription under a wide variety of circumstances. According to our current understanding, PARP1 becomes active following BRCT domain-mediated dimerization (Buki 1995, Mendoza-Alvarez 1993) by recognizing and binding to DNA nicks or double-stranded breaks. The PARP⧸LigIII-type Zn fingers located in the DNA-binding domain (see Fig. 1) mediate damage recognition. Upon binding, a conformational change in the protein is proposed

Specificity of Transcriptional Activation

It is now clear that PARP helps induce many genes during developmental and adult life. Interestingly, most PARP-dependent genes mediate rapid responses to environmental factors such as stress, infection, nutrition, or hormonal signals. PARP might be specifically required when chromatin needs to be changed rapidly or to be under precise control. However, it remains possible that it is a general transcription factor (Meisterernst et al., 1997) that plays a major role only when genes must be

Heterochromatin Condensation

The wide distribution of PARP protein along chromosomes and its overall abundance suggests that it may play a structural role even when inactive. The effects of mutating parp-e in Drosophila strongly support this hypothesis (Tulin et al., 2002). DAPI-stained chromatin in parp-e mutant larval cells appears abnormally extended (Fig. 8a) and is more accessible to nuclease digestion. Heterochromatic regions rich in repetitive DNA sequences that normally condense early in development are

Concluding Thoughts

In this review, we have discussed evidence linking PARP to many fundamental processes governing chromosome structure, function, and maintenance. Although the models discussed remain speculative, PARP can no longer be viewed primarily as an enzyme of DNA repair. Why, then, has PARP evolved to serve such a wide variety of critical functions involving chromatin organization? We suggest that PARP is inherently different from other enzymes that modify target chromatin proteins, such as kinases,

Acknowledgements

We thank J. Gall for providing materials. This work was supported by NIH Grant GM27875. We apologize to those whose work was not cited due to space limitations.

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Regulation of Chromatin Structure and Gene Activity by Poly(ADP-Ribose) Polymerases

Abstract

Introduction

Section snippets

Poly(ADP-Ribose) Polymer Metabolism

Mechanism of Action

Poly(ADP-Ribose) Polymerase and Transcription

Multiple Routes to Poly(ADP-Ribose) Polymerase Activation

Specificity of Transcriptional Activation

Heterochromatin Condensation

Concluding Thoughts

Acknowledgements

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