1 Health and Environment Unit, Faculty of Medicine, Laval University Medical Research Center, 2705 Boulevard Laurier, Ste-Foy, QC, G1V 4G2, Canada
2 Health Canada, HPFB, Biologics and Genetic Therapies Directorate, Centre for Biologics Research, Cellular and Molecular Biology Division, AL2201C, Sir FG Banting Research Laboratories, Tunney's Pasture, Ottawa, ON, K1A OL2, Canada
* Author for correspondence (e-mail: guy.poirier{at}crchul.ulaval.ca)
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Summary |
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Key words: PARP, PARG, poly(ADP-ribose), poly(ADP-ribosyl)ation, chromatin, histones
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Introduction |
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Chromatin structure provides a serious obstacle to virtually every aspect of genomic activity, be it replication, transcription, recombination or repair. Yet, this hierarchical structure is malleable, in that local domains can be made accessible in response to various stimuli, and dynamic, in that histones can be deposited, exchanged and chemically modified to accommodate specific activities. In addition, variants of all of the major histones have been identified and each can substitute for its counterpart at specific chromatin locations to define a particular biological context (reviewed by Ausió et al., 2001; Redon et al., 2002
; Smith, 2002
). CENP-A, for example, is an H3 homologue associated with centromeric regions (Sullivan et al., 1994
). H2AX is an H2A variant that becomes phosphorylated (and then termed
H2AX) in response to DNA double-strand breaks, where it forms foci with other proteins involved in DNA repair (Redon et al., 2002
). MacroH2A is an H2A variant preferentially associated with the inactive X-chromosome (Costanzi and Pehrson, 1998
; Ladurner, 2003
). The non-uniform composition of chromatin reflects the complexity of processes being carried out at any given time in particular areas of the genome.
Structural transitions in chromatin also depend on the core domains of histones, which are responsible for the compaction of DNA and for establishing protein-protein interactions (Arents and Moudrianakis, 1995). These core domains are flanked by variable N- and C-terminal regions that can be acetylated, methylated, ubiquitylated, phosphorylated and poly(ADP-ribosyl)ated (van Holde, 1988
; Wu and Grunstein, 2000
; Zlatanova et al., 2000
). Defining the precise combination of post-translational covalent modifications encountered on specific sets of histones has led to the formulation of a `histone code' hypothesis (reviewed by Lizuka and Smith, 2003
; Turner, 2002
; Lachner et al., 2003
), in which discreet histone modification patterns orchestrate the recruitment of specific factors or modules required for particular processes. Poly(ADP-ribosyl)ation reactions have not been included in the histone code primarily because stimulation of poly(ADP-ribose) polymerase-1 (PARP-1; the major enzyme responsible for this type of post-translational modification) activity and poly(ADP-ribosyl)ation of linker histone H1 are most apparent following the introduction of DNA strand breaks. Consequently, this has restricted discussion of the biological significance of poly(ADP-ribosyl)ation to detection and signalling of low-to-moderate levels of DNA damage and to energy depletion under catastrophic DNA damage conditions (see below) (reviewed by D'Amours et al., 1999
; Szabo and Dawson, 1998
). However, recent findings challenge this view and suggest that histone poly(ADP-ribosyl)ation plays a more fundamental role in genomic activity (Tulin and Spradling, 2003
; Kraus and Lis, 2003
).
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Poly(ADP-ribose) polymerases and poly(ADP-ribosyl)ation |
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PARP-1 is an abundant, 113 kDa nuclear protein comprising an N-terminal DNA-binding domain, a central automodification domain and a C-terminal catalytic domain. The DNA-binding domain, characterized by the presence of two zinc fingers and a nuclear localization signal, plays a crucial role in the recognition of DNA strand breaks and concomitant activation of PARP-1 (Benjamin and Gill, 1980; Ikejima et al., 1990
) (reviewed by D'Amours et al., 1999
). The automodification domain comprises a BRCT module that mediates several protein-PARP-1 interactions. This domain is found in numerous proteins involved in the DNA damage response and cell-cycle checkpoint. PARP-1 automodification thus regulates both protein-PARP-1 and DNA-PARP-1 interactions. The most dramatic elevations in PARP-1 activity are mediated by single-strand breaks, although significant stimulation also occurs following recognition of double-strand breaks (Weinfeld et al., 1997
). The ensuing 10 to 500-fold rise in poly(ADP-ribose) synthesis translates DNA damage into intracellular signals that trigger DNA repair and/or cell death pathways. In conditions of low-to-moderate levels of DNA damage, the activation of PARP-1 causes rapid self-poly(ADP-ribosyl)ation and covalent modification of histones and other chromatin proteins (Table 1). Modified proteins lose their affinity for DNA owing to the high negative charge of poly(ADP-ribose). These events are believed to `prime' the damaged site for the subsequent repair of DNA single-strand breaks by base excision repair (BER). Although the exact functions of PARP-1 and poly(ADP-ribose) in BER remain to be fully deciphered, several lines of evidence support roles in local chromatin remodelling, protection of DNA breaks, and recruitment and modulation of the activity of repair factors, including XRCC1, DNA ligase III, DNA polymerase ß and FEN-1, which are part of the BER complex (Dantzer et al., 2000
; Lavrik et al., 2001
; Prasad et al., 2001
; El-Khamisy et al., 2003
; Leppard et al., 2003
; Okano et al., 2003
). By contrast, in conditions of excessive DNA damage, massive poly(ADP-ribose) synthesis can cause a rapid depletion of cellular NAD+ pools and impairment of NAD-dependent cellular functions, such as glycolysis and mitochondrial respiration. In an attempt to restore NAD+ levels, cells deplete their ATP pools, thereby creating an insurmountable energy shortage resulting in cell death (reviewed by Chiarugi, 2002
). Therefore, PARP-1 may be considered a molecular switch for life or death. Moreover, PARP-1 might allow damaged cells to choose between apoptotic and necrotic mechanisms of cell death. PARP-1 is proteolyzed by caspases 3 and 7 to generate a 24 kDa DNA-binding domain and a 89 kDa catalytic domain during the early `execution' phase of apoptotic cell death (Kaufmann et al., 1993
). This cleavage event prevents DNA repair and the ensuing energy depletion that would otherwise induce necrosis, because the DNA-binding domain competes with PARP-1 for binding to DNA strand breaks (Yung et al., 2001; D'Amours et al., 2001
). The roles of PARP-2 in BER and cell death are less well characterized, but its functions appear to parallel those of PARP-1: PARP-2 is a component of the BER complex (Schreiber et al., 2002
) and it too contains a short N-terminal DNA-binding domain, a C-terminal automodification/catalytic domain and a caspase 3 cleavage site at the junction between these two domains (Ménissier-de Murcia et al., 2003
).
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Poly(ADP-ribose) polymer also non-covalently associates with nuclear proteins. Histones, heterogeneous nuclear ribonucleoproteins, the tumour suppressor p53, p21Cip1/Waf1 and lamins all specifically bind both to free poly(ADP-ribose) and poly(ADP-ribose) covalently attached to automodified PARP-1 (Pleschke et al., 2000; Gagné et al., 2003
). This unexpected behaviour is mediated by a novel binding motif consisting of alternating hydrophobic and basic residues, which confers affinity for poly(ADP-ribose) (Fig. 2) (Pleschke et al., 2000
). Although these non-covalent interactions have yet to be demonstrated to occur in vivo, the identification of the poly(ADP-ribose)-binding motif in proteins involved in chromatin architecture (e.g. histones) and in DNA repair (e.g. DNA ligase III and XRCC1) (Pleschke et al., 2000
) supports the concept of poly(ADP-ribose) serving as a scaffold for the recruitment and assembly of DNA repair machinery (see below) (reviewed by Lindahl et al., 1995
; Leppard et al., 2003
).
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The consequence of poly(ADP-ribosyl)ation: condensation or relaxation of chromatin? |
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Early studies suggested that poly(ADP-ribosyl)ation leads to condensation of chromatin (Stone et al., 1977; Nolan et al., 1980
; Butt et al., 1980
; Wong et al., 1983
). However, other work suggested that it relaxes chromatin (Poirier et al., 1982a
; Aubin et al., 1983
; de Murcia et al., 1986
). Following studies in vitro observing isolated nuclei and purified polynucleosomes, condensation of chromatin was postulated to occur through the formation of covalent histone H1 dimers linked by poly(ADP-ribose) chains of 15 residues (Stone et al., 1977
; Nolan et al., 1980
; Butt et al., 1980
). At the time, analysis of the poly(ADP-ribosyl)ated histone H1 dimer complex relied almost exclusively on gel electrophoresis techniques. However, the strong anionic properties and high molecular weight of long-chain poly(ADP-ribose), compounded with its propensity to intermesh with chromatin proteins during preparation and electrophoretic fractionation, might have been underestimated. In fact, the electrophoretic patterns of partially poly(ADP-ribosyl)ated H1 and of `suspected' histone H1 dimer preparations treated with poly(ADP-ribose) glycohydrolase (PARG) were best reconciled by the idea that there is a modified species consisting of a single heavily poly(ADP-ribosyl)ated H1 (de Murcia et al., 1986
).
Subsequent visualization by electron microscopy clearly established that poly(ADP-ribosyl)ated chromatin adopts a more relaxed structure than its native counterpart (Poirier et al., 1982a; Aubin et al., 1983
; de Murcia et al., 1986
). When isolated polynucleosomes are poly(ADP-ribosyl)ated in vitro by a highly purified preparation of PARP-1 at low and moderate ionic strengths, the former adopts the fully extended `beads on a string' structure characteristic of H1-depleted chromatin (Fig. 3A,B) (Poirier et al., 1982a
; de Murcia et al., 1986
), and subsequent studies have confirmed that the poly(ADP-ribose) chromatin is indeed `relaxed' (de Murcia et al., 1986
).
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Poly(ADP-ribosyl)ated histone H1 remains associated with relaxed chromatin (Poirier et al., 1982a). Significantly, the chromatin relaxation induced by poly(ADP-ribosyl)ation of histone H1 is fully reversible following degradation of poly(ADP-ribose) by exogenous PARG (Fig. 3C) (de Murcia et al., 1986
). Whereas histone H1 is the preferred substrate upon maximal activation of PARP-1, it has been demonstrated that core histones H2A and H2B can be poly(ADP-ribosyl)ated in the presence of low NAD+ concentrations (10 µM), as well as in chromatin depleted of histone H1, suggesting that histones can be sequentially or differentially poly(ADP-ribosyl)ated depending on the levels of substrate NAD+ and PARP-1 automodification/activation (Huletsky et al., 1985
; Huletsky et al., 1989
) (A. Fréchette, Modulation de la chromatine par la poly(ADP-ribose) polymérase endogène du pancréas du rat, PhD thesis, Sherbrooke University, QC, Canada, 1983). In an in vitro poly(ADP-ribose) turnover assay in which exogenous PARP-1 and PARG are supplied to chromatin fragments, core histones H2A and H2B become preferentially modified at the expense of histone H1 (Thomassin et al., 1992
). These observations strongly support a model in which low, physiological levels of activation of PARP-1 favour poly(ADP-ribosyl)ation of nucleosome cores and establishment of a local area of structural plasticity, whereas overt stimulation, such as when the genome accumulates DNA strand breaks, leads to hyper-modification of linker histone H1 and concomitant dramatic relaxation of the chromatin architecture.
But what of the non-covalent interactions between histones and poly(ADP-ribose) (Althaus, 1992)? This type of physical interaction appears to be stronger and more specific than would be predicted on the basis of electrostatic interactions alone, suggesting that the polymer might be endowed with `scaffolding' properties. The affinities for poly(ADP-ribose) are in the order H1>H2A>H2B=H3>H4 (Panzeter et al., 1993
). As stated earlier, the C-terminal domain of histone H1, which is involved in generating higher-order chromatin structure (Thoma et al., 1983
), mediates binding to poly(ADP-ribose) (Fig. 2) (Althaus, 1992
). Interestingly, 40 ADP-ribose residues covalently attached to PARP-1 apparently suffice to disrupt a chromatosome fully (Realini and Althaus, 1992
; Althaus, 1992
). The affinity of histones for poly(ADP-ribose), especially on automodified PARP-1, led to the proposal of a `histone shuttle' mechanism for chromatin relaxation/recondensation involving poly(ADP-ribose) (Realini and Althaus, 1992
). According to this scenario, poly(ADP-ribose) synthesized on PARP-1 activated by DNA strand breaks at the site of damage could locally dissociate histones from chromatin. Poly(ADP-ribose) would then serve as a scaffold onto which histones could be sequestered in order to facilitate repair. Subsequent cleavage of poly(ADP-ribose) by PARG would then allow histone-DNA complexes to reform. Data to support this model are offered by Realini and Althaus (1992
). Furthermore, we have observed that H1 remains associated with chromatin relaxed by poly(ADP-ribosyl)ation in vitro (Poirier et al., 1982a
; Aubin et al., 1983
). The possibility that automodified PARP-1 can act as a scaffold for the transient and local sequestration of histones within relaxed chromatin domains, and by extension for the recruitment of enzymes and co-factors, is attractive, not only in the context of repair, but also for replication and transcription.
Recent reports by the Spradling laboratory (Tulin et al., 2002; Tulin and Spradling, 2003
) have elegantly linked PARP-1 activation to the generation of polytene chromosome puffs and transcriptional activation of the cognate ecdysone, HSP70 and NF-
B-dependent immune response loci in Drosophila. These data extend other recent demonstrations that PARP-1 functions as a classical transcriptional regulator/co-regulator in certain promoter contexts (reviewed by Kraus and Lis, 2003
) and strengthen the case for poly(ADP-ribosyl)ation acting as a widespread chromatin structure remodelling mechanism allowing access to specific areas of the genome. Interestingly, poly(ADP-ribosyl)ation has been shown to antagonize DNA methylation and maintain heterochromatin in a relatively relaxed state (Zardo et al., 1997
; Zardo and Caiafa, 1998
; de Capoa et al., 1999
). Inhibition of poly(ADP-ribosyl)ation results in hypermethylation and increased compaction of heterochromatin, a phenomenon possibly attributable to H1e, a variant of histone H1 that corresponds to H1.1 in human cells (d'Erme et al., 1996
).
Several lines of evidence also suggest that PARPs and/or poly(ADP-ribose) contribute directly to higher-order folding of chromatin fibres. Proteins of the nuclear scaffold, such as lamins (Adolph and Song, 1985a; Adolph and Song, 1985b
; Pedraza-Reyes and Alvarez-Gonzalez, 1990) and topoisomerase II (Kaufmann et al., 1991
; Scovassi et al., 1993
), are poly(ADP-ribosyl)ated. Moreover, PARP-1 is itself tightly associated with the nuclear matrix (Kaufmann et al., 1991
) and binds to matrix attachment regions (MARs) involved in the formation of chromatin loop domains (Galande and Kohwi-Shigematsu, 1999
). PARP-1 not only binds and is activated strongly by DNA strand breaks but binds efficiently to supercoiled DNA as well (Gradwohl et al., 1987
). Located strategically at MARs, PARP-1 could contribute significantly to the modulation of higher-order chromatin organization. HMG proteins of the nucleosomal-binding domain family, HMGN1 and HMGN2 (formerly called HMG 14 and 17) (Bustin, 2001
), are also good substrates for PARP-1 (D'Amours et al., 1999
), have high affinity for nucleosomal DNA (Wolffe, 1998
) and, consequently, have been proposed to influence chromatin folding. Recent findings also support a fundamental role for PARP in the global organization of chromatin and, more specifically, of heterochromatin and repetitive sequences (Tulin et al., 2002
). PARP-mutant Drosophila cells lack nucleoli, which is consistent with the fact that PARP-1 is abundant in the nucleolar region (Lamarre et al., 1988
; Fakan et al., 1988
) and the idea that PARP-1 is important in the functional compartmentalization of the nucleus.
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Poly(ADP-ribose) glycohydrolase and chromatin recondensation |
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Other enzymes might also cleave poly(ADP-ribose). Snake venom phosphodiesterase, for example, cleaves the adjoining phosphates of ADP-ribose units (Miwa and Sugimura, 1982). Although endogenous mammalian equivalents have been little characterized (Futai et al., 1968
), their contribution to poly(ADP-ribose) catabolism should not be overlooked. The recent description of the macro domain structure found in histone macroH2A and in several putative PARPs (Aravind, 2001
) suggests that this domain has phosphoesterase activity directed towards poly(ADP-ribose) (Ladurner, 2003
; Allen et al., 2003
). Interestingly, cleavage of poly(ADP-ribose) by a nuclear phosphodiesterase is predicted to leave a terminal phosphate group that could not be further cleaved by PARG or extended by a PARP. Such an event might allow the cell to `tag' specific proteins irreversibly in order to secure their function, as has been proposed for silencing of the X-chromosome by histone macroH2A (Allen et al., 2003
).
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Links to further aspects of chromatin function |
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The early work of Slattery et al. identified PARP-1 as a component of the transcription initiation complex required for the suppression of random transcription initiation by RNA polymerase II (Slattery et al., 1983). The RAP30 and RAP74 subunits of the general transcription factor TFIIF have also been documented to serve as polymer acceptors (Rawling and Alvarez-Gonzalez, 1997
), which suggests that PARP-1 is also involved in regulating the elongation phase of transcription. This notion has recently been reinforced by Vispé et al., who have demonstrated an attenuating role for PARP-1 during this process (Vispé et al., 2000
). The recent demonstration of recruitment and activation of PARP-1 at specific inducible promoters in Drosophila (Tulin et al., 2002
; Tulin and Spradling, 2003
), along with a growing list of reports of physical interactions between PARP-1 and promoter/enhancer elements and transcription factors (including NF-
B, B-myb, Oct-1, AP-2, RXR
nuclear receptors, HTLV Tax-1 protein, PC1, E47, YY1, DF-1, TBP and TEF-1) (reviewed by Bürkle et al., 2000
; Kraus and Lis, 2003
), several of whose DNA-binding and functional properties are affected by poly(ADP-ribosyl)ation, provides further support for the central involvement of PARP in regulating the transcriptional activities of genes, above and beyond its requirement as a modulator of chromatin structure (reviewed by D'Amours et al., 1999
; Hassa and Hottiger, 2002
; Bouchard et al., 2003
; Kraus and Lis, 2003
). The contributions of the scaffolding properties of poly(ADP-ribose) and the potential synergy between PARPs and other known chromatin-associated molecular complexes such as `mediator', SWI/SNF or FACT in this process represent exciting areas of future inquiry. Moreover, recent findings add coordination of development, centromere function, stabilization/inactivation of the X-chromosome, regulation of telomere length and apoptosis to the list of cellular processes requiring fine tuning of chromatin folding by poly(ADP-ribosyl)ation without excluding an active and direct role of PARPs in each of these.
Development
The redundancy of mammalian PARPs has hindered the deciphering of cellular functions for PARP-1 and poly(ADP-ribose) in knockout mouse models (Shall and de Murcia, 2000). Although acutely sensitive to
-irradiation, neither PARP-1 nor PARP-2 knockout mice display overtly abnormal phenotypes (Shall and de Murcia, 2000
; Ménissier-de Murcia et al., 2003
). In sharp contrast, Parp-1/Parp-2/ double-mutant mice die during early embryogenesis, which suggests that they have overlapping essential functions during normal mammalian development (Ménissier-de Murcia et al., 2003
). Similarly, disruption of the single PARP gene in Drosophila is lethal at the larval stage (Tulin et al., 2002
).
Centromeres
PARP-1 and PARP-2 have both been detected at centromeres, where they interact with constitutive (CENP-A and CENP-B) and facultative (Bub3) centromeric proteins. Interestingly, CENP-A replaces histone H3 in at least a subset of centromeric nucleosomes. These centromeric proteins are poly(ADP-ribosyl)ated during radiation-induced DNA damage (Saxena et al., 2002a; Saxena et al., 2002b
). Moreover, CENP-A bears a sequence matching the poly(ADP-ribose) consensus binding sequence, which suggests that it can also interact non-covalently with poly(ADP-ribose) (Fig. 2) (Saxena et al., 2002a
). PARP-1 is distributed broadly over centromeres and extends to pericentromeric regions, whereas PARP-2 localization is discrete (Saxena et al., 2002a
; Saxena et al., 2002b
). Although the biological function of PARP-1 and PARP-2 at centromeres remains to be defined, it has been observed that Parp-2/ mice subjected to
-irradiation show an increase in centromeric chromatid breaks (Ménissier-de Murcia et al., 2003
). Because PARP-2 is involved in BER (Schreiber et al., 2002
), the authors propose that PARP-2 helps to maintain centromeric DNA integrity (Ménissier-de Murcia et al., 2003
). In addition, because centromeres are sites for organization of the kinetochores that facilitate attachment and alignment of chromosomes on spindle microtubules, chromatin remodelling directed by PARP-1 and PARP-2 might be required for this process. The latter hypothesis is supported by the detection of chromosome segregation and kinetochore defects in Parp-2/ embryos (Ménissier-de Murcia et al., 2003
). Another interesting observation was that female Parp-1+/ Parp-2/ embryos are obtained at a frequency lower than expected when Parp-1+/ mice are crossed with Parp-2+/ mice. This correlates with constitutive instability of the X-chromosome and is attributed to defective segregation and aberrant fusion of the X-chromosome with autosomal chromosomes (Ménissier-de Murcia et al., 2003
). Whether this is due to PARP-2-specific functions at centromeres that can only be rescued partially by PARP-1, or whether this is a consequence of a defect of BER or recombination repair, remains to be defined. An equally attractive proposal might be that both PARPs are required to establish and maintain a pattern of X-chromatin-specific (ADP-ribosyl)ation, part of which could be shared with autosomal chromatin, which when lost could render cues for mitotic segregation uninterpretable.
Telomeres
Telomere integrity is essential for chromosome maintenance. Telomeres consist of long tandem arrays of repeats bound by specialized telomeric proteins that contribute to the formation of the characteristic t-loop and to the protection and replication of the telomeric DNA (Chan and Blackburn, 2002). PARP-1, tankyrase 1 and tankyrase 2 all localize to telomeres, and recent data suggest that poly(ADP-ribose) synthesis helps to maintain telomeric DNA (Smith et al., 1998
; Smith and de Lange, 1999
; Cook et al., 2002
). Tankyrase 1 and tankyrase 2 interact with TRF1, a cis-acting, negative regulator of telomere length and poly(ADP-ribosyl)ate it (Smith et al., 1998
; Cook et al., 2002
). Overexpression of either tankyrase in the nucleus releases poly(ADP-ribosyl)ated TRF1 and allows telomere elongation, suggesting that tankyrases are positive regulators of telomere length.
A poly(ADP-ribose)-binding sequence has also been identified within the catalytic domain of human TERT (Pleschke et al., 2000), the enzymatic component of telomerase responsible for telomere elongation. Although physical association between poly(ADP-ribose) and TERT remains to be demonstrated, it is tempting to speculate that telomeric poly(ADP-ribose) synthesis downregulates the activity of the telomerase. This notion could be extended to the telomerase-independent function of TERT in telomere capping (reviewed by Chan and Blackburn, 2002
).
Apoptosis
PARP-1 has been implicated in both caspase-dependent and apoptosis-inducing factor (AIF)-directed cell death (D'Amours et al., 1999; Yu et al., 2002
; Candé et al., 2002
). During the execution phase of caspase-dependent apoptosis, PARP-1 is inactivated following cleavage by caspase 3 and caspase 7, which releases its DNA-binding domain from its catalytic domain. PARP-2 apparently suffers the same fate in HL-60 cells, albeit several hours after PARP-1 (Ménissier-de Murcia et al., 2003
). The inactivation of PARP-1 and PARP-2 has several consequences. One is that PARP-1 inactivation should halt further depletion of cellular NAD+ and ATP that would otherwise lead to necrotic cell death, increased damage to neighbouring cells and inflammation. Inactivation of PARP-1 and PARP-2 should also decrease the ability of the cell to repair DNA damage and increase the rate of apoptotic cell death. Whether this should be attributed to a drop in enzyme activity or formation of a tight ternary complex at the site of damage remains to be determined. PARP-1 and PARP-2 inactivation might also influence the rate of internucleosomal DNA fragmentation, nuclear shrinkage and chromatin condensation (Affar et al., 2000
), possibly by modulating the activities of endonucleases. However, poly(ADP-ribose) might also compete with DNA for nuclease binding. We have observed that micrococcal nuclease digestion of chromatin is favoured in the absence of poly(ADP-ribosyl)ation (Aubin et al., 1983
), whereas others have observed an increased sensitivity of heterochromatin repetitive sequences in Drosophila that do not express PARP (Tulin et al., 2002
).
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Conclusions and perspectives |
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The frequent identification of PARP-1 as a component of replication, repair and transcription complexes certainly supports the view that it is part of several specialized machineries within the nucleus (reviewed by D'Amours et al., 1999; Hassa and Hottiger, 2002
; Kraus and Lis, 2003
). Associations with PCNA, p53, p21Waf1/Cip1, Cockayne syndrome B protein and chromatin assembly factor-1 (CAF-1) (Flohr et al., 2003
; Frouin et al., 2003
; Okano et al., 2003
; Wieler at al., 2003
) offer the equally exciting possibility that it is also part of a more general machinery. It will be interesting, therefore, to characterize these associations and determine how PARP-1 and PARP-2 activities and/or the scaffolding properties of poly(ADP-ribose) contribute to the function(s) and composition of these modules. The availability of Parp-1/ and Parp-2/ mice (Ménissier-de Murcia et al., 2003
) and of new PARP inhibitors, highly specific and hydrosoluble, will certainly facilitate such studies (reviewed recently by Virág and Szabó, 2003
; Rouleau and Poirier, in press
). Finally, the identification of multiple PARPs, the interplay between PARP-1 and PARP-2, and the presence of catalytically active macro domains targeting poly(ADP-ribose) in histone variants make including poly(ADP-ribosyl)ation in the histone code a tantalizing prospect.
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Acknowledgments |
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References |
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