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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Genet Dev. Author manuscript; available in PMC 2011 October 1.
Published in final edited form as:
PMCID: PMC2942995

The roles of PARP1 in gene control and cell differentiation


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.


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 (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 non-covalent manner [1012] 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.

Figure 1
Schematic illustration showing PARP1 roles in chromatin gene expression control

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 promoter regions of numerous genes [21]. As illustrated by in vivo and in vitro studies, extensive PARP1 binding to nucleosomes makes chromatin more dense and compact, thus preventing the transcription machinery from initiating gene transcription (Figure 2A). This phenomenon is variously supported in the literature. For example, adding recombinant PARP1 to purified chromatin in vitro changes the conformation of the chromatin from an open state to a more condensed state [22]. In vivo studies showed that PARP-1 is associated with both Drosophila and mouse Hsp70 genes before heat shock treatment when transcription is repressed [8, 23]. In addition, Drosophila PARP1 is required for silencing the transcription of the transposable elements and endogenous retroviruses in heterochromatin [5, 24]. When mouse PARP-1 was enriched, it was found to be necessary for stable gene silencing on the inactive X chromosome [25]. PARP1 was also localized to other constitutive heterochromatin regions, including the centromeres [26] and telomeres [27]. The heterochromatin protein HP1α also interacted with PARP1 and PARP2 on pericentric heterochromatin in mammalian cells [28]. Therefore, cumulative evidence suggests that PARP1 is an essential component of chromatin for the repression of transcription locally in euchromatin and more globally in the heterochromatin when its enzymatic activity is not activated (Figure 2A).

Figure 2
Transcription control by PARP1 through chromatin modulation

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 activation can best be illustrated in the hrp70 loci in Drosophila. Upon heat shock, PARP1 was potently activated, and pADPr signals were detected in the heat-shock induced puffs [8], which, in turn, resulted in PARP1 dissociation from the puffs [8]. This appears to be the main mechanism for the rapid loss of nucleosomes covering a larger region around the hrp70 genes upon heat shock [30]. Loss of nucleosomes induced by heat shock may result from automodified PARP1 dissociation from H3 and H4, which are binding sites for inactive PARP1 [20], further destabilizing nucleosome structure (Figure 2B).

Automodified PARP1 also acts as a platform to bind with histone variants for modulating chromatin structure (Figure 2). The histone variant macroH2A1 (mH2A1) has a homologous histone domain for assembly into the nucleosome and a unique macrodomain for interaction with other chromatin modifiers [31]. mH2A1 is enriched on the inactive X chromosome and many developmental genes on autosomes for repressing gene transcription by making chromatin more compact [32]. A dynamic interaction between mH2A1 and PARP1 appears to exist in the organism to modulate chromatin structure. On the one hand, mH2A1 inhibits PARP1 activity both in the promoter of the hsp70 gene [23] and on the inactive X chromosome in mice, which leads to transcription inhibition [25] (Figure 2A). On the other hand, once PARP1 is activated by, for example, DNA damage, automodifed PARP1 binds to mH2A1.1 through its macrodomain, thereby recruiting mH2A1.1 to PARP1 activation sites for chromatin transient condensation [13]. However, mH2A1 is dissociated from the promoter of the hsp70 gene upon heat shock when PARP1 is activated [23]. Thus, for developmentally regulated genes, it is more likely that poly(ADP-ribosyl)ation of mH2A facilitates the release of mH2A1.1 from repressive chromatin regions for transcription activation (Figure 2B).

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 Spt16 disrupts the association of FACT with the nucleosome and inhibits FACT-mediated exchange of histone variant H2AX with canonical H2A [33, 34]. In addition, ATP-dependent nucleosome remodeling complexes, including ISWI and ALC1, modulate chromatin structure by nucelosome sliding [14, 38]. An unbiased genetic screen showed that the Parp1 and Parg mutations enhanced the rough-eye phenotype caused by eye-specific expression of the dominant negative allele ISWIk159R, suggesting the genetic interaction between ISWI and PARP1 or PARG genes [35, 39]. Biochemical assays showed that ISWI can be poly(ADP-ribosyl)ated in vitro and that poly(ADP-ribosyl)ated ISWI can be detected in vivo (Figure 2B). It appears that poly(ADP-ribosyl)ation inhibits the ATPase activity of ISWI and further reduces its binding affinity for nucleosomes [35]. It has been shown in vivo that ISWI can promote histone H1 binding to chromatin and thus help to compact it [40]. However, since H1 also competes with PARP1 for binding to the gene promoters [21], poly(ADP-ribosyl)ation of ISWI may actually counteract H1 binding by relaxing chromatin after PARP1 activation (Figure 2B). In addition, two independent studies suggested that pADPr can bind with ALC1 (amplified in liver cancer 1) through its macrodomain by an in vitro binding assay [14, 36]. In contrast to the inhibition of ISWI ATPase activity and binding affinity for nucleosomes by poly(ADP-ribosyl)ation [35], PARP1-mediated pADPr binding with ALC1 strongly stimulated its ATPase and nucleosome-sliding activities and helped to recruit ALC1 to DNA damage sites, possibly for the purpose of relaxing chromatin [14, 36]. Notwithstanding these findings, the mechanism underlying the stimulation of ALC1 activity by automodified PARP is not entirely understood. However, since the nucleosome-sliding ability of ALC1 is dependent on H4 tail, we speculate that destabilization of mononucleosomes by automodified PARP may expose the histone H4 tail, thus allowing interaction with ALC1 for its activity in vivo [14]. Therefore, besides histone and its variants, it is clear that activated PARP1 also can interact with, and modulate the activities of, a number of nucleosome-remodeling factors to further destabilize chromatin and facilitate transcription activation (Figure 2B).

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 alternative splicing by binding with exonic and intronic splicing silencers (ESEs and ISEs) and enhancers (ESSs and ISSs), respectively [41]. Our studies and those of others suggest that poly(ADP-ribose) also binds with hnRNPs and SR protein to regulate their functions [15, 16, 42] (Figure 3). A proteomic approach was used to identify hnRNPs as the most abundant pADPr-binding proteins through a conserved motif localized between two RNA-binding domains in human HeLa cells [42]. Using mass spectrometry analysis, Drosophila Hrp38, a homolog of hnRNP A1, was also found to be associated with PARP1 protein [20]. In addition, Drosophila PARP1 overexpression and PARG loss-of-function both result in increased amounts of hnRNPs (hrp38 and hrp40) bound to pADPr in vivo, suggesting that PARP and PARG activities can regulate pADPr binding to hnRNPs [15]. Interestingly, heat-shock treatment, which activates PARP1, also upregulates the ability of pADPr binding to hnRNPs and further causes the dissociation of hnRNPs from most of the transcripts in the nucleus. As a consequence, pADPr binding to hnRNPs inhibits the RNA-binding ability of hnRNPs and further modulates the alternative splicing pathway [15] (Figure 3A). It was also found that pADPr can bind with the alternative splicing factor/splicing factor 2 (ASF/SF2, a prototypical SR protein) through two functional domains (RRM1 and RS) [16].

Figure 3
Splicing regulation by poly(ADP-ribosyl)ation of the splicing proteins

ASF/SF2 has an SR-rich C-terminal domain where serine residues are often phosphorylated by multiple kinases, including DNA Topoisomerase I, to regulate splicing [43]. It appears that pADPr inhibits ASF/SF2 phosphorylation by blocking the kinase activity of DNA [16]. Therefore, pADPr binding to SR proteins may also regulate alternative splicing by modulating phosphorylation of SR protein or directly influencing the affinity for RNA binding (Figure 3B). Indeed, an in silico study also revealed that mammalian Parp-1 knockout cells have an increased incidence of alternative splicing within a subset of inflammatory response genes [16]. Considering that transcription and splicing are closely coupled [44], poly(ADP-ribosyl)ation of the splicing proteins (hnRNPs and SR protein) by locally activated PARP1 may regulate alternative splicing pathway in a the spatial- and temporal-specific manner.

PARP1 controls developmental processes

Drosophila PARP1 loss-of-function has caused larval lethality [5], and mouse PARP-1 and PARP-2 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 signals, such as hormone secretion [47], can induce PARP1 activation during development. Therefore, chromatin modulation by activated PARP1 regulates the transcription and splicing of genes in different cell types and at different developmental stages.

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 receptors (EcR/USP), which further acts on the ecdysone response element of the induced genes [49]. PARP1 protein is present in the region surrounding the E74-75B loci, but high levels of poly(ADP-ribose) only appear after the inducible expression of the E74 and E75 genes, suggesting that PARP1 is activated for the transcription of ecdysone-inducible genes [8]. It appears that PARP1 interacts with the ecdysone receptor in vivo and is associated with the promoter region of one ecdysone-inducible gene (hsp27) [50]. In addition, Drosophila nucleosome remodeling factor (NURF)-specific subunit NURF301 is required for transactivation of the ecdysone-inducible genes [51]. A recent study showed that chromatin structure in the upstream region of the E75 gene exhibits a dramatic change, including H3 and nucleosome depletion upon ecdysone induction [52]. Therefore, by the interaction with histones and NURFs, activated PARP1 may destabilize nucleosome structure in the chromatin region of ecdysone-inducible genes, which, in turn, facilitates ligand-EcR/USP complex binding to EcR elements of ecdysone-inducible genes for transactivation.

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 PARP2 null male mice have lower fertility as a result of severe defects of spermiogenesis [54]. Interestingly, PARP2 null spermatocytes exhibited defective meiotic sex chromosome inactivation (MSCI) shown by retaining RNA polymerase II on the XY body and upregulation of X- and Y-linked gene expressions, suggesting that PARP2 is involved in the maintenance of MSCI [54]. Indeed, PARP2 and macroH2A1 are colocalized on the XY body [54]. In fact, it was found that mouse PARP-1 is enriched and is required for gene silencing on the inactive X chromosome where its enzymatic activity is inhibited by macroH2A1[25]. Thus, it will be interesting to further investigate the roles of PARP1 and PARP2 for the establishment of X chromosome inactivation.

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 differentiation, poly(ADP-ribosyl)ates the transcription factor Sox2 to control the expression level of fibroblast growth factor 4 (FGF4) [56]. PARP1, PARP2 and their activities are also required for the differentiation of mouse embryonic carcinoma F9 cells into endodermal cells. Both PARP1 and PARP2 can poly(ADP-ribosyl)ate one isoform of heterochromatin protein 1(HP1α) to recruit the transcriptional intermediary factor (TIFIβ) to pericentric heterochromatin for the expression of the endoderm-specific gene during endodermal differentiation [28]. Therefore, PARP1 also plays important roles in cell differentiation.


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 chromatin-remodeling factors to further modulate chromatin. As a coupled reaction with transcription, splicing is also regulated by PARP1 through poly(ADP-ribosyl)ation of the splicing proteins. The functions of PARP1 in transcription and splicing control are reflected in multiple roles during development, including metamorphosis, gametogenesis and cell differentiation. In the future, more effort should be directed to investigate the developmental roles of PARP1 in the context of chromatin modulation.


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 A.V.T.).


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