Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation

https://doi.org/10.1016/j.ceb.2008.03.006Get rights and content

The regulation of gene expression requires a wide array of protein factors that can modulate chromatin structure, act at enhancers, function as transcriptional coregulators, or regulate insulator function. Poly(ADP-ribose) polymerase-1 (PARP-1), an abundant and ubiquitous nuclear enzyme that catalyzes the NAD+-dependent addition of ADP-ribose polymers on a variety of nuclear proteins, has been implicated in all of these functions. Recent biochemical, genomic, proteomic, and cell-based studies have highlighted the role of PARP-1 in each of these processes and provided new insights about the molecular mechanisms governing PARP-1-dependent regulation of gene expression. In addition, these studies have demonstrated how PARP-1 functions as an integral part of cellular signaling pathways that culminate in gene-regulatory outcomes.

Introduction

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant (as many as 1–2 million copies per cell [1]) and ubiquitous nuclear enzyme with biochemical properties that make it ideally suited for the regulation of nuclear processes. Although originally characterized as a key factor in DNA repair pathways, a wealth of studies over the past decade have demonstrated a role for PARP-1 in the regulation of gene expression under basal, signal-activated, and stress-activated conditions [1, 2, 3]. Recent studies using a variety of experimental approaches have highlighted the role of PARP-1 in at least four distinct modes of transcriptional regulation (see below) and provided new insights about the cellular signaling systems that interface with PARP-1 in the nucleus.

PARP-1, the founding member of the PARP superfamily [4], has a carboxyl-terminal catalytic domain that polymerizes linear or branched chains of ADP-ribose (ADPR) from donor nicotinamide adenine dinucleotide (NAD+) molecules on target proteins (Figure 1) [1, 2]. Poly(ADP-ribosyl)ation (PARylation) by PARP-1 is probably the major source of poly(ADP-ribose) (PAR) production in the cell [1]. PARP-1 also has an amino-terminal DNA-binding domain (DBD) containing two zinc finger motifs, as well as a central automodification domain (AMD) that functions as the target of direct covalent automodification [1, 4] (Figure 1a). Together, these domains allow PARP-1 to interact with genomic DNA and chromatin, poly(ADP-ribosyl)ate relevant nuclear targets, and regulate gene expression. Studies from the past few years, which will be the focus of this review, have begun to elucidate the underlying mechanisms and consequences of gene regulation by PARP-1.

Section snippets

PARP-1 activities and interactions

The biochemical activities of PARP-1 provide clues to how it might function in gene regulation in vivo. High affinity binding of PARP-1 to certain forms of DNA (double-strand breaks, cruciforms, crossovers) and nucleosomes are mediated by the DBD [1, 3, 5, 6•, 7, 8]. PARP-1's enzymatic activity is low in basal or unstimulated conditions, but is potently allosterically activated by the binding of PARP-1 to a variety of interaction partners, including proteins, nucleosomes, and the aforementioned

PARP-1 genomics

Understanding the role of PARP-1 in gene regulation requires knowledge of where PARP-1 binds in the genome and which genes are directly regulated by its actions. Recent genomic studies have begun to provide answers to these questions. Chromatin immunoprecipitation coupled to hybridization to genomic microarrays (i.e. ChIP-chip) has shown that PARP-1 binding is enriched at the promoters of perhaps as many as 90% of expressed RNA polymerase II (Pol II)-transcribed promoters in MCF-7 cells [18••].

Modulation of chromatin structure and composition by PARP-1

The earliest characterized effects of PARP-1 on the genome were the modulation of chromatin structure and the PARylation of histones [1, 3, 26, 27] (Figure 2a). The effects of PARP-1 on chromatin structure have been elaborated and elucidated in more recent biochemical and in vivo studies [5, 6•, 28, 29]. For example, biochemical assays have shown that PARP-1 binds to nucleosomes at the dyad axis with a stoichiometry of 1 [5]. Saturated PARP-1 binding to nucleosomes in the absence of NAD+

Enhancer-binding actions of PARP-1

Many of the initial studies describing direct effects of PARP-1 on the transcriptional regulation of target genes focused on the binding of PARP-1 to specific DNA sequences or structures in the regulatory regions of the genes, allowing PARP-1 to function like a classical enhancer-binding factor [32, 33, 34, 35, 36] (Figure 2b). In fact, direct binding of PARP-1 to hairpins may underlie an autoregulatory mechanism governing the expression of the PARP-1 gene itself [37]. Two recent studies have

Transcriptional coregulation by PARP-1

Roles for PARP-1 as a promoter-specific coregulator (either a coactivator or a corepressor) for a number of different sequence-specific DNA-binding transcriptional regulators, such as NF-κB, nuclear receptors, HES1, B-Myb, Oct-1, HTLV Tax-1, Sp1, NFAT, Elk1, and others, have been reported [2, 3, 12, 13, 40, 41, 42, 43••] (Figure 2c). In most of these cases, the DNA-binding factor is thought to recruit PARP-1 to relevant target promoters. Yet, ChIP-chip analyses have shown that many peaks of

Insulator functions of PARP-1: CTCF, the nuclear matrix, and DNA methylation

Insulators are DNA elements that help to organize the genome into discrete regulatory units by limiting the effects of enhancers on promoters or by preventing the spread of heterochromatin [46]. Recent studies have implicated PARP-1-dependent PARylation of CTCF, a ubiquitous DNA-binding protein that functions at insulators, in the preservation of insulator function [16, 17, 47] (Figure 2d). In this regard, the general PARP inhibitor 3-aminobenzamide blocks insulator function in cell-based

Signaling and regulation in PARP-1-dependent gene expression pathways

A number of cellular signaling pathways culminate with the regulation of PARP-1-dependent transcriptional processes (Figure 4). Mediating signals include small molecules (e.g. steroid and vitamin hormones) [13, 23••], peptide hormones and cytokines, heat shock [15••, 29], and kinases (e.g. CaM kinase IIδ and ERK2) [12, 43••]. Cellular signaling may result in the post-translational modification of PARP-1 through autoPARylation [43••], acetylation [56], or phosphorylation [57•, 58], which alter

Conclusions

The available data indicate that PARP-1 regulates transcription in perhaps as many as four modes: first, as a modulator of chromatin structure by binding to nucleosomes, modifying histone proteins, or regulating the composition of chromatin; second, as an enhancer-binding factor that functions in a manner similar to classical sequence-specific DNA-binding activators or repressors; third, as a transcriptional coregulator that functions in a manner similar to classical coactivators and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author thanks Matthew Gamble, Kristine Frizzell, and Raga Krishnakumar for their critical comments and helpful suggestions. The author's laboratory is supported by funding from the National Institute of Diabetes, Digestive, and Kidney Disorders.

References (62)

  • V.A. Soldatenkov et al.

    Transcriptional repression by binding of poly(ADP-ribose) polymerase to promoter sequences

    J Biol Chem

    (2002)
  • O.A. Olabisi et al.

    Regulation of transcription factor NFAT by ADP-ribosylation

    Mol Cell Biol

    (2008)
  • K. Zaniolo et al.

    Regulation of poly(ADP-ribose) polymerase-1 (PARP-1) gene expression through the post-translational modification of Sp1: a nuclear target protein of PARP-1

    BMC Mol Biol

    (2007)
  • B.G. Ju et al.

    A breaking strategy for topoisomerase IIbeta/PARP-1-dependent regulated transcription

    Cell Cycle

    (2006)
  • F.R. Althaus

    Poly(ADP-ribose): a co-regulator of DNA methylation?

    Oncogene

    (2005)
  • A.C. Bell et al.

    Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene

    Nature

    (2000)
  • P.O. Hassa et al.

    Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-κB-dependent transcription

    J Biol Chem

    (2005)
  • M.E. Bonicalzi et al.

    Regulation of poly(ADP-ribose) metabolism by poly(ADP-ribose) glycohydrolase: where and when?

    Cell Mol Life Sci

    (2005)
  • D. D’Amours et al.

    Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions

    Biochem J

    (1999)
  • M.Y. Kim et al.

    Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal

    Genes Dev

    (2005)
  • J.C. Amé et al.

    The PARP superfamily

    Bioessays

    (2004)
  • D.A. Wacker et al.

    The DNA binding and catalytic domains of poly(ADP-ribose) polymerase 1 cooperate in the regulation of chromatin structure and transcription

    Mol Cell Biol

    (2007)
  • I. Lonskaya et al.

    Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding

    J Biol Chem

    (2005)
  • M.F. Langelier et al.

    A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation

    J Biol Chem

    (2008)
  • B.G. Ju et al.

    Activating the PARP-1 sensor component of the groucho/TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway

    Cell

    (2004)
  • R. Pavri et al.

    PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of Mediator

    Mol Cell

    (2005)
  • T.M. Yusufzai et al.

    CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species

    Mol Cell

    (2004)
  • R. Krishnakumar et al.

    Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes

    Science

    (2008)
  • H. Ogino et al.

    Loss of Parp-1 affects gene expression profile in a genome-wide manner in ES cells and liver cells

    BMC Genomics

    (2007)
  • B. Zingarelli et al.

    Absence of poly(ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury

    Mol Med

    (2003)
  • Z.Q. Wang et al.

    Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease

    Genes Dev

    (1995)
  • Cited by (0)

    View full text