Elsevier

Molecular Aspects of Medicine

Volume 34, Issue 6, December 2013, Pages 1124-1137
Molecular Aspects of Medicine

Review
Poly-ADP-ribose polymerase: Machinery for nuclear processes

https://doi.org/10.1016/j.mam.2013.04.001Get rights and content

Abstract

It is becoming increasingly clear that the nuclear protein, poly-ADP-ribose polymerase 1 (PARP1), plays essential roles in the cell, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Despite the exciting progress made in understanding the ubiquitous role of poly-ADP-ribose metabolism, a basic mechanism of PARP’s activity regulating multiple nuclear processes is yet to be outlined. This review offers a holistic perspective on activity of PARP1, based on empirically observable phenomena. Primary attention is given to mechanisms by which PARP1 regulates a broad range of essential nuclear events, including two complementary processes (1) regulation of protein–nucleic acid interactions by means of protein shuttling and (2) utilizing poly-ADP-ribose as an anionic matrix for trapping, recruiting, and scaffolding proteins.

Introduction

The molecular processes occurring within the eukaryotic nucleus primarily revolve around the maintenance and utilization of nucleic acid, a remarkable species of molecules having the capacity to store chemical information and consequently propagate an organism’s self-sustained existence. Such maintenance and utilization of nucleic acid is based upon its interaction with proteins: another remarkable group of molecules having the ability to catalyze countless chemical reactions. Nuclear processes center upon this orchestrated protein–nucleic acid dance.

Poly-ADP-ribose (pADPr) was first discovered 50 years ago and has been gracefully called the third nucleic acid (Chambon et al., 1963, D’Amours et al., 1999). The polymer is a structure consisting of ADP-ribose units and several points of branching with 20–25 residues per branch (reaching up to 200 residues in total) linked by glycosidic ribose–ribose 1″-2′ bonds (Gonzalez and Jacobson, 1987). It consists of one mole of adenosine per two moles of ribose and two moles of phosphate making pADPr twice as negatively charged as DNA or RNA (Reeder et al., 1967, Sugimura et al., 1967). Its residues are capable of base stacking and forming hydrogen bonds (Kanai et al., 1978, Sibley et al., 1986). Unlike DNA and RNA, pADPr does not have an ability to store chemical information, but rather mimic their biochemical behavior. pADPr is synthesized by poly-ADP-ribose polymerases (PARPs) using NAD+, covalently attaching units of ADP-ribose to both itself and acceptor proteins via glutamic acid residues. PARPs have been shown to play essential roles in numerous nuclear processes, including chromatin remodeling, transcription, DNA repair, DNA synthesis, telomere maintenance, and translation. Because of likely functional redundancies, the presence of 17 paralogous PARPs in mammals (Amé et al., 2004, Tulin et al., 2003) greatly complicates their analysis. Fortunately, model organisms, such as Drosophila, (Adams et al., 2000) have a single nuclear PARP1 ortholog of mammalian PARP1, making this animal an invaluable model system to study PARP1 functions. Because PARP1 function in Drosophila system is understood most comprehensively, this review will focus primarily on findings of Drosophila studies, discuss how these findings complement observations made in mammalian systems, as well as their relevance and limitations to understanding poly(ADP-ribose) polymerase activity in mammals.

This review is meant to offer a holistic perspective on the mechanisms by which PARP1 activity regulates a broad range of essential nuclear processes. The effects of PARP1 activity on nuclear processes will be discussed in the context of regulating protein–nucleic acid interaction by means of protein shuttling (Chambon et al., 1963) and utilizing poly-ADP-ribose (Amé et al., 2000, D’Amours et al., 1999) as an anionic matrix for trapping, recruiting and scaffolding proteins.

Section snippets

Background: enzymes and activities

First discovered in the 1960s (Chambon et al., 1963), the role of chromatin modification by pADPr remained mysterious for a long time. The basic enzymatic reactions catalyzed by PARP1 involve transferring ADPr from NAD to either a protein acceptor or an existing pADPr chain (Fig. 1). The modification target is most commonly the COOH residue of a glutamic acid in proteins, although other amino acids may be modified as well. The average pADPr chain length is 20–25 residues (Gonzalez and Jacobson,

Histones control PARP1 protein in chromatin

After the histones, PARP1 is the most abundant nuclear protein. The pool of freely diffusible nucleoplasmic PARP1 is very small, with most of the PARP1 protein bound to chromatin and accumulated in nucleoli (Molinete et al., 1993, Dantzer et al., 1998, Tulin and Spradling, 2003, Kim et al., 2004, Pinnola et al., 2007). The distribution of PARP1 in chromatin is nonrandom, occurring in characteristic profiles specific for distinct cell types. The molecular basis for PARP1 targeting to chromatin

PARP1 covalently modifies nuclear proteins

PARP1 can modify proteins both covalently and noncovalently; that is to say, a protein’s function or localization can be dramatically changed either by the covalent attachment of poly-ADP-ribose or noncovalent interaction with it. Approximately thirty proteins have been identified, both in vivo and in vitro, as covalent targets of poly-ADP-ribosylation (D’Amours et al., 1999). The proteins include a broad range of components and regulators in key nuclear processes: modulating chromatin

PARP1 modulate nucleosomal stability

One of the most dramatic effects of protein shuttling by PARP1 involves the process of opening (loosening) chromatin. Eukaryotic DNA is tightly packaged by histones into the complex chromatin. When the cell needs to access DNA for repair or transcription, the packaged DNA needs to be opened. Substantial evidence has implicated poly-ADP-ribosylation in the process of histone shuttling and subsequent chromatin decondensation in which poly-ADP-ribose attracts histones away from DNA (Poirier et

Other nuclear protein shuttling by PARPS

Although PARP1 activity plays a major role in chromatin loosening in response to multiple environmental or developmental cues, it is also necessary for regulating protein-nucleic acid interaction in several other nuclear events. In eukaryotic cells, mRNA splicing involves the excision of introns in forming a mature mRNA transcript for translation. This process enables the cell to create a variety of proteins from a single gene by differentially splicing the transcribed RNA. Messenger RNA

Poly-ADP-ribose as a matrix: recruitment and scaffolding

The strong attraction between various proteins and poly-ADP-ribose, specific or nonspecific, is seen as having essential consequences other than mediating protein–nucleic acid interaction. As a heavily branched, anionic polymer, it is becoming increasingly clear that poly-ADP-ribose acts both as a place of origin for various nuclear processes—a point of protein recruitment—and an environment in which the processes can occur.

Concluding remarks

Because PARP1 plays essential roles in regulating nuclear processes, its mechanisms of operation provide us with a platform from which to study how these events are coordinated for normal function of a living cell. This review offers a comprehensive discussion of PARP1 functions at a fundamental level, examining the basic methods of operation by which PARP1 regulates nuclear processes. The fundamental mechanical effects of PARP1 activity have been discussed as two complementary phenomena: (1)

Acknowledgements

We thank Dr. Kate Pechenkina for critical reading of the manuscript and valuable comments. The expenses were defrayed by a Grant from the National Institutes of Health (R01 GM077452) (to A.V.T.).

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