The roles of PARP1 in gene control and cell differentiation

https://doi.org/10.1016/j.gde.2010.06.001Get rights and content

Cell growth and differentiation during developmental processes require the activation of many inducible genes. However, eukaryotic chromatin, which consists of DNA and histones, becomes a natural barrier impeding access to the functional transcription machinery. To break through the chromatin barrier, eukaryotic organisms have evolved the strategy of using poly(ADP-ribose) polymerase 1 (PARP1) to modulate chromatin structure and initiate the steps leading to gene expression control. As a structural protein in chromatin, enzymatically silent PARP1 inhibits transcription by contributing to the condensation of chromatin, which creates a barrier against gene transcription. However, once activated by environmental stimuli and developmental signals, PARP1 can modify itself and other chromatin-associated proteins, thereby loosening chromatin to facilitate gene transcription. Here we discuss the roles of PARP1 in transcriptional control during development.

Introduction

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear protein created by eukaryotes to manage the structure and function of high order chromatin. The PARP1 protein, which is conserved among eukaryotes [1] except in yeast [2], utilizes NAD+ as substrate to synthesize poly(ADP-ribose) polymer (pADPr) with the resulting sizes varying from 2 to 200 ADP-ribose units [3]. The mammalian genome contains additional PARP superfamily members, PARP2–PARP17 [4], while the Drosophila genome encodes only two PARP superfamily members: a single nuclear PARP1 and a single cytoplasmic PARP5 (Tankyrase) [5]. PARP1 can modify target proteins by essentially attaching a poly(ADP-ribose) (pADPr) chain to itself through Glu/Asp [6] and/or lysine residues [7] in its automodification domain (Figure 1a). It is this accumulation of pADPr which leads to local chromatin loosening [8••, 9] and facilitates transcription by RNA polymerase II (Pol2) (Figure 1b). Although automodified PARP1 (pADPr-PARP1) loses its enzymatic capabilities in this process, it gains the ability to bind proteins through conserved pADPr-binding domains in a noncovalent manner [10, 11, 12] to further modulate chromatin [13••, 14••] and regulate RNA maturation steps [15••, 16•]. An antagonist of PARP1, poly(ADP-ribose) glycohydrolase (PARG), degrades the pADPr polymer and regulates the level of poly(ADP-ribosyl)ated proteins within chromatin and nucleoplasm [17, 18] (Figure 1b). In this review, we focus on recent studies of PARP1 functions under normal physiological condition and explain how nuclei can utilize the ability of PARP1 protein to modulate chromatin for transcription and splicing control during development.

Section snippets

PARP1 as the chromatin protein for transcription inhibition

In steady-state conditions, most PARP1 proteins are associated with chromatin and are accumulated in nucleoli [8••, 9, 19]. Numerous studies suggest that PARP1 binds to the core histone proteins (H2A, H2B, H3 and H4) in the nucleosome [20, 21]. Specifically, the C-terminal domain of PARP1 preferentially interacts with H3 and H4, an event not mediated by DNA but negatively regulated by the N-terminal domain of PARP1 [20]. In contrast, PARP1 and H1 compete with each other for binding to the

Interaction of activated PARP1 with histones for chromatin modulation

Many environmental and developmental signals can activate PARP1 during an organism's development. Because poly(ADP-ribose) is highly negatively charged and has a high binding affinity for its associated proteins [29], automodifed PARP1 and subsequent interactions with histones and their variants dramatically change the structure of chromatin from a condensed state to a less concentrated (i.e. ‘loose’) state which facilitates gene transcription (Figure 2). Chromatin remodeling by PARP1

Poly(ADP-ribosyl)ation of chromatin-remodeling factors for chromatin modulation

PARP1 can also modify several chromatin-remodeling factors, including Spt16 in the FACT (facilitates chromatin transcription) complex [33•, 34•] and the nucleosome-remodeling ATPases, ISWI [35••] and ALC1 (amplified in liver cancer 1) [14••, 36]. The FACT complex, a heterodimer of hSpt16 and SSRP1, is associated with the nucleosome and facilitates transcription elongation by removing one H2A–H2B dimer to enable the passage of pol II through the chromatin [37]. Upon DNA damage,

Poly(ADP-ribosyl)ation of the splicing proteins for splicing regulation

In addition to its direct effects on chromatin and transcription, as described above, PARP1 also mediates the follow-up steps of gene expression via regulation of proteins involved in RNA processing. Alternative splicing is used extensively to produce the different mRNA isoforms of a gene to increase the complexity of the transcriptome in higher eukaryotic genomes. It is generally believed that two groups of RNA-binding proteins, hnRNPs and serine-arginine-rich (SR) splicing factor, regulate

PARP1 controls developmental processes

Drosophila PARP1 loss-of-function has caused larval lethality [5], and mouse PARP1 and PARP2 double knockout mice died at the early embryonic stages [45], suggesting that poly(ADP-ribosyl)ation is essential for normal development. Although PARP1 is constitutively expressed, its enzyme activity is developmentally regulated. For example, the maximal accumulation of pADPr was observed at the prepupal stage in Drosophila [46]. Both exogenous stimuli, such as heat shock [8••], and endogenous

PARP1 controls metamorphosis in Drosophila

The developmental roles of PARP1 were illustrated in the observation that PARP1 enzymatic activity is required for chromatin loosening on ecdysone-inducible loci (E74 and E75) in Drosophila [8••]. At the end of the wandering third larval stage in Drosophila, a pulse of ecdysone triggers puparium formation and the onset of metamorphosis by inducing the expression of E74, E75 and BR-C genes [48]. The transcriptional activation is achieved by ecdysone binding to a heterodimer of two nuclear

PARPs in germline development

PARPs also play roles in germline development, including oogenesis and spermiogenesis. During meiosis, it appears that PARP1 had dynamic localization patterns in mouse oocytes, which correlates with transcription state [53]. PARP1 null oocytes showed meiotic defects, including persistent H2AX phosphorylation, suggesting a role of PARP1 for chromatin modification during ooctye maturation [53]. Because of the redundant function of PARP1 with PARP2, PARP1 null female mice are fertile [53], but

PARP1 in cell differentiation

A number of studies have also demonstrated that PARP1 and poly(ADP-ribosyl)ation are involved in cell differentiation. After injection into nude mice, parp−/− embryonic stem (ES) cells can differentiate to form teratocarcinoma-like tumors with the characteristics of trophoblast giant cells, suggesting that PARP1 may inhibit ES cell differentiation into trophoectodermal cells in the wild type [55]. However, a recent study showed that PARP1, whose activity is upregulated during ES cell

Summary

PARP1 performs a dual function in transcription control. First, as the essential component of chromatin, PARP1 represses transcription locally in euchromatin and more globally in the heterochromatin. Second, once activated by developmental cues, automodified PARP1 interacts with histone H3 and H4 and their variants, such as macroH2A1, to destabilize chromatin structure in order to allow the transcription machinery to operate. In addition, activated PARP1 also poly(ADP-ribosyl)ates several

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

We thank Dr Hua-Ying Fan for her critical reading of the manuscript and valuable comments. The expenses were defrayed by a grant from the National Institutes of Health (R01DK082623) (to AVT).

References (56)

  • H. Otto et al.

    In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs)

    BMC Genomics

    (2005)
  • E. Perkins et al.

    Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast

    Cancer Res

    (2001)
  • D. D’Amours et al.

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

    Biochem J

    (1999)
  • J.C. Amé et al.

    The PARP superfamily

    BioEssays

    (2004)
  • A. Tulin et al.

    The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development

    Genes Dev

    (2002)
  • Z.P. Tao et al.

    Identification of the ADP-ribosylation sites in the PARP-automodification domain: analysis and implications

    J Am Chem Soc

    (2009)
  • M. Altmeyer et al.

    Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites

    Nucleic Acids Res

    (2009)
  • A. Tulin et al.

    Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci

    Science

    (2003)
  • M.Y. Kim et al.

    NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1

    Cell

    (2004)
  • I. Ahel et al.

    Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins

    Nature

    (2008)
  • G. Timinszky et al.

    A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation

    Nat Struct Mol Biol

    (2009)
  • D. Ahel et al.

    Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1

    Science

    (2009)
  • Y. Ji et al.

    Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins modulates splicing

    Nucleic Acids Res

    (2009)
  • M. Malanga et al.

    Poly(ADP-ribose) binds to the splicing actor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I

    J Biol Chem

    (2008)
  • S. Hanai et al.

    Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster

    Proc Natl Acad Sci U S A

    (2004)
  • A. Tulin et al.

    Drosophila poly(ADP-ribose) glycohydrolase mediates chromatin structure and SIR2-dependent silencing

    Genetics

    (2006)
  • V.S. Meder et al.

    PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli

    J Cell Sci

    (2005)
  • R. Krishnakumar et al.

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

    Science

    (2008)
  • Cited by (0)

    View full text