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First published online February 12, 2004
doi: 10.1242/10.1242/jcs.01080

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Poly(ADP-ribosyl)ated chromatin domains: access granted

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

View larger version (23K): [in a new window]   Fig. 1. Metabolism of poly(ADP-ribose). Poly(ADP-ribose) polymerase-1 (PARP-1) hydrolyzes NAD+ to polymerize ADP-ribose units on substrate proteins, with the concomitant release of nicotinamide. PARP-1 catalyzes the three steps of poly(ADP-ribose) anabolism (red part of the cycle): (1) mono(ADP-ribosyl)ation of the acceptor protein substrate; (2) elongation; and (3) branching of the poly(ADP-ribose) chain. Branching occurs on average every 20-50 ADP-ribose units (Alvarez-Gonzalez and Jacobson, 1987). The catalytic activities of other PARPs remain to be characterized. They catalyze mono and poly(ADP-ribosyl)ation reactions but may not all be able to carry out the branching reaction. The negatively charged poly(ADP-ribose) has a short half-life owing to poly(ADP-ribose) glycohydrolase (PARG) (green side of the cycle) that is activated by an increase in the cellular concentration of poly(ADP-ribose). PARG carries exoglycosidic and endoglycolytic activities that cleave glycosidic bonds between ADP-ribose subunits located at the ends and within the poly(ADP-ribose) chains, respectively (cleavage sites shown by dark green arrows). The release of the most proximal ADP-ribose unit from the acceptor protein (cleavage site shown by the light green arrow) can be catalyzed by PARG (Desnoyers et al., 1995) and/or by ADP-ribosyl protein lyase (Oka et al., 1984).

View larger version (34K): [in a new window]   Fig. 2. Schematic representation of human histone poly(ADP-ribosyl)ation sites. The positions of covalent modification sites (branched structures) for human histones H1 and H2B have been predicted from corresponding rat coordinates (Riquelme et al., 1979; Ogata et al., 1980a; Ogata et al., 1980b). The amino acid sequences of non-covalent poly(ADP-ribose)-association sites identified from in vitro studies are shown for H2A, H2B, H3 and H4 (Pleschke et al., 2000). Putative binding sites are shown for H1, macroH2A and CENP-A. They correspond to the sequence best matching the consensus–KRXHXBXHHBBHHBX– (Pleschke et al., 2000), where H is a hydrophobic amino acid, B is a basic amino acid and X is any amino acid. There may be more than one poly(ADP-ribose)-binding site in H1. Positions of the histone fold (ovals) and tail regions are according to Arents and Moudrianakis (Arents and Moudrianakis, 1995) for H2A, H2B, H3 and H4 and approximated for H1, macroH2A and CENP-A. The macro domain of macroH2A is represented by a diamond. (Human histone sequence accession numbers: H1.2: P16403; H2A: P02261; macroH2A2: Q9P0M6; H2B: P02278; H3: P16106; CENP-A: P49450; H4: P02304.)

View larger version (105K): [in a new window]   Fig. 3. Electron microscopic visualization of the modulation of chromatin structure induced by synthesis and degradation of poly(ADP-ribose). The condensed chromatin superstructure (A) was relaxed by a 60 minute incubation with purified poly(ADP-ribose) polymerase in the presence of 200 µM NAD (B). Poly(ADP-ribosyl)ated chromatin re-condensed by a 60 minute incubation with purified poly(ADP-ribose) glycohydrolase (C). The arrows in (B) point to automodified PARP-1 molecules. Chromatin was fixed and spread in 40 mM NaCl. Bar, 0.1 µm. Reproduced with permission from de Murcia et al. (de Murcia et al., 1986).

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