Correlation between endogenous nucleosomal hyper(ADP-ribosyl)ation of histone H1 and the induction of chromatin relaxation.

Aubin, R. J.; Fréchette, André; Murcia, Gilbert de; Mandel, P.; A, Lord; Grondin, Gilles; Poirier, Guy G.

doi:10.1002/j.1460-2075.1983.tb01643.x

Cited by 74 publications

(42 citation statements)

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“…Considerable evidence suggests that PARP1 directly interacts with histones (3). For example, histones H1, H2A, and H2B are preferential targets for PARP1 binding in vitro (33), and they are enzymatically modified by PARP1 (34)(35)(36). However, Drosophila histone H1 was recently reported as an antagonist of PARP1 binding to chromatin (28).…”

Section: Zn-finger Domain 1 Is Necessary For the Silencing Of Retrotrmentioning

confidence: 99%

Uncoupling of the transactivation and transrepression functions of PARP1 protein

Kotova

Jarnik

Tulin

2010

Proc. Natl. Acad. Sci. U.S.A.

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Poly(ADP ribose) polymerase 1 (PARP1) is a nuclear protein that regulates chromatin remodeling and transcription as well as DNA repair and genome stability pathways. Recent studies have revealed a paradoxical dual role of PARP1 protein in transcription. Specifically, although PARP1 controls transcriptional activation of a subset of genes that are heat shock-or hormone-dependent, it also directly inactivates transcription, establishes heterochromatin domains, and silences retrotransposable elements. However, the domains required for these disparate functions are currently unknown. In this paper, we report the discovery of a previously undescribed mutation in the Drosophila Parp locus. We show that the mutants express a deletion mutant of PARP1 protein with an altered DNA binding domain that carries only the second Znfinger. We demonstrate that this alteration specifically excludes PARP1 protein from heterochromatin and makes PARP1 unable to maintain repression of retrotransposable elements. By characterizing the biological activity of this unique PARP1 mutant protein isoform, we have uncoupled the transactivation and transrepression functions of this protein.chromatin | poly(ADP ribose) polymerase | transcription P oly(ADP ribose) polymerase 1 (PARP1) protein has been known for decades as a nuclear protein that recognizes and binds nicks and ends of DNA and catalyses poly(ADP ribose) (pADPr) synthesis (1). The basic enzymatic reactions catalyzed by PARP1 involve transferring ADPr from nicotinamide-adenine dinucleotide to either a protein acceptor or an existing pADPr chain, the average length of which is 80 or more residues (2). PARP1 protein can modify numerous chromatin proteins in vivo and in vitro (3). A key role of PARP1 was shown in DNA repair and apoptosis (3), where PARP works as a trigger between the DNA repair (4) and apoptotic pathways (5). PARP1 enzymatic activity has also been shown to be required for normal assembly of higher order chromatin structures and for transcriptional activation (6). Moreover, it has been shown that PARP1 regulates the transcription of these genes by inducing chromatin loosening at targeted genetic loci (6, 7). Finally, PARP1 establishes silent chromatin domains and represses retrotransposable elements (8).The characterization of deletion mutants of PARP that distinguish among the varied functions of this protein is essential to establish a more complete understanding of PARP1 protein biology. At present, however, we have identified neither the mechanism of PARP protein targeting to specific chromatin domains nor the mechanism of local PARP activation. Closing these gaps in our current knowledge is complicated because the presence of 18 paralogous PARP proteins (9) in mammals most likely results in corresponding functional redundancies. The Drosophila genome (8, 10, 11) encodes only a single nuclear PARP (PARP1), making this animal an invaluable model system for the study of PARP functions.The PARP1 protein has three functionally defined domains conserved from human to Droso...

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Section: Zn-finger Domain 1 Is Necessary For the Silencing Of Retrotrmentioning

confidence: 99%

Uncoupling of the transactivation and transrepression functions of PARP1 protein

Kotova

Jarnik

Tulin

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Poly ADP-ribosylation of these proteins in vitro reversibly alters their DNA binding affinity (10)(11)(12)(13)(14)(15). Enzymatic addition and removal of ADP-ribose polymers on chromatin preparations in vitro induces reversible relaxation of polynucleosomes (16), the relaxation state being directly related to the size of histone-bound ADP-ribosyl polymers (17)(18)(19). Histones are also a physiological target of ADP-ribose modifications in carcinogen-treated mammalian cells in vivo (20,21).…”

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confidence: 99%

Uncoupling of DNA excision repair and nucleosomal unfolding in poly (ADP-ribose)-depleted mammalian cells

Mathis

Althaus

1990

Carcinogenesis

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The repair of DNA damage in eukaryotic cells is closely coupled with local changes of chromatin structure such that newly synthesized repair patches transiently appear in 'free' DNA domains with increased accessibility to enzymatic and chemical probes. We have isolated these domains from mammalian cells repairing bulky DNA adducts. During the first 3 h of repair, excision of adducts occurred exclusively in free DNA and was closely linked with the appearance of newly synthesized repair patches. Following depletion of chromatin-bound poly(ADP-ribose), the repositioning of repair patches into these domains was completely blocked, although overall repair patch synthesis was unaltered. Concomitantly, DNA adducts were no longer excised and tended to accumulate in free DNA domains. Our results suggest a tight coupling of the excision step with the formation of free DNA domains by a mechanism involving poly ADPrnbosylation of chromatin proteins.In chromatin of mammalian cells, newly synthesized DNA repair patches exhibit a transient micrococcal nuclease hypersensitivity. This hypersensitivity is thought to reflect local disruptions in the tightly packed nucleosomal organization of chromatin, causing exposure of 'free' DNA domains (for review see 1,2). The function of these domains as well as the mechanisms involved in their formation are unknown. We have speculated that the post-translational poly ADP-ribosylation of chromatin proteins might be involved in the formation of free DNA domains in DNA excision repair. Poly ADP-ribosylation is catalyzed by the enzyme poly(ADP-ribose)polymerase (1,3,4; EC 2.4.2.30). Following activation by DNA nicks, this enzyme operates in a strictly processive manner (5). Continuous treatment of living cells with benzamide, a competitive inhibitor of this enzyme (3,4,6), results in the degradation of chromatin-bound ADP-ribose polymers (7) by the enzyme poly(ADP-ribose)glycohydrolase (3,4). Using non-replicating adult rat hepatocytes in primary monolayer culture, we have established conditions for the complete depletion of chromatin-associated poly(ADP-ribose) (7,8). Hepatocytes survive up to 9 days under these conditions and maintain expression of liver-specific functions (8). Thus, poly(ADPribose)-depleted hepatocytes represent a convenient model system to study the role of poly ADP-ribosylation in specific steps of DNA repair.We have previously shown that unfolded free DNA domains can be isolated from the chromatin of intact mammalian cells by taking advantage of their preferential accessibility to 8-methoxypsoralen (9). Upon intercalation into free DNA domains of living cells, 8-methoxypsoralen can be photoactivated to form bifunctional DNA adducts crosslinking the two DNA strands. Crosslinked (free) DNA domains can then be isolated quantitatively following a denaturation/renaturation treatment and subsequent nuclease SI digestion of non-crosslinked DNA strands (for details see 9).Here we have isolated free DNA domains from non-replicating hepatocytes (9

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“…tion of histone H1, using either exogenously added purified calf thymus enzyme [ 161 or the intrinsic poly(ADP-ribose) polymerase [17]. In addition we found recently that in vitvo the activity of topoisomerase I, an enzyme implicated in DNA replication, transcription, modification of chromatin structure in vivo [18, 191, was decreased in parallel to the extent of its ADP-ribosylation [20].…”

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confidence: 97%

“…In addition we found recently that in vitvo the activity of topoisomerase I, an enzyme implicated in DNA replication, transcription, modification of chromatin structure in vivo [18, 191, was decreased in parallel to the extent of its ADP-ribosylation [20]. All these results reinforced the suggestion of an involvement of poly(ADP-ribosylation) in vivo in DNA metabolism and gene expression through alterations of the chromatin structure.The mechanism of the relaxation process is not known but it has been shown with the endogenous poly(ADP-ribose) polymerase, to be dependent on the concentration of NAD and correlated with the formation of hyper-ADP-ribosylated forms of histone HI [17]. At NAD concentrations above 100 pM partially relaxed polynucleosomes can be seen and the hyper-ADP-ribosylated forms of histone HI predominated [17].…”

mentioning

confidence: 99%

“…The mechanism of the relaxation process is not known but it has been shown with the endogenous poly(ADP-ribose) polymerase, to be dependent on the concentration of NAD and correlated with the formation of hyper-ADP-ribosylated forms of histone HI [17]. At NAD concentrations above 100 pM partially relaxed polynucleosomes can be seen and the hyper-ADP-ribosylated forms of histone HI predominated [17].…”

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confidence: 99%

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Time course of polynucleosome relaxation and ADP‐ribosylation

Niedergang

Murcia

Ittel

et al. 1985

European Journal of Biochemistry

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Isolated rat pancreatic polynucleosomes were poly(ADP-ribosylated) with purified calf thymus poly(ADPribose) polymerase. A time course study was performed using an NAD concentration of 200 pM and changes in nucleosomal structure were investigated by means of electron microscopy visualization and sedimentation velocity determinations. In parallel, analyses of histone H1 poly(ADP-ribosylation) and determinations of DNA polymerase CI activity on ADP-ribosylated polynucleosomes were done at different time intervals.A direct kinetic correlation between ADP-ribose incorporation, polynucleosome relaxation amd histone HI hyper-ADP-ribosylation was established. In addition, DNA polymerase CI activity was highly stimulated on ADPribosylated polynucleosomes as compared to control ones, suggesting increased accessibility of DNA to enzymatic action.Because of the strong evidence implicating histone HI in the maintenance of higher-ordered chromatin structures, the present study may provide a basis for the interpretation of the involvement of the histone HI ADP-ribosylation reaction in DNA rearrangements during DNA repair, replication or gene expression.Poly(ADP-ribose) polymerase, an enzyme ubiquitous to eucaryotes, catalyses the synthesis of a homopolymer of ADP-ribose units at the expense of the cellular NAD pool. The poly(ADP-ribose) formed is generally covalently bound to various nuclear proteins, mainly the enzyme itself and histones, and it has been suggested to be involved in DNA replication, DNA repair and cell differentiation (for reviews, see [I -41).Post-translational modifications of histones, i. e. phosphorylation, acetylation and poly(ADP-ribosylation), may be potential modulators of the nucleosomal structure during DNA transcription and replication (for reviews, see [5 -71). Amongst the histones it was suggested that given the localization of histone HI at the region of entry and exit of the nucleosomal DNA, this histone would stabilize the nucleosomal structure such as to modulate, and subsequently maintain, the organization and higher-order coiling transitions of a polynucleosomal chain into a helix or solenoid of pitch 11 nm [8, 91 (see also the Discussion).We focused on histone poly(ADP-ribosylation) since poly(ADP-ribose) polymerase is believed to be located preferentially in the internucleosomal regions of chromatin [ 10, 111 and, amongst the histones, HI is the best acceptor of poly(ADP-ribose) in vitro in isolated nuclei [12-141 and in vivo in untreated tissue [I 51. Moreover, ADP-ribosylation was recently shown to cause the relaxation of the polynucleosome structure in vitvo, presumably through its effect of modificaAbbreviations. ADP-ribose, adenosine(5')diphospho(5)-P-~-ribose; poly(ADP-ribose), polymer of ADP-ribose.Enzymes. Poly(ADP-ribose) polymerase (EC 2.4.99.-); micrococcal nuclease (EC 3.1.31.1); DNA polymerase c( (EC 2.7.7.7); pyruvate kinase (EC 2.7.1.40).tion of histone H1, using either exogenously added purified calf thymus enzyme [ 161 or the intrinsic poly(ADP-ribose) polymerase [17]. I...

show abstract

Correlation between endogenous nucleosomal hyper(ADP-ribosyl)ation of histone H1 and the induction of chromatin relaxation.

Cited by 74 publications

References 65 publications

Uncoupling of the transactivation and transrepression functions of PARP1 protein

Uncoupling of the transactivation and transrepression functions of PARP1 protein

Uncoupling of DNA excision repair and nucleosomal unfolding in poly (ADP-ribose)-depleted mammalian cells

Time course of polynucleosome relaxation and ADP‐ribosylation

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