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PARP1 ADP-ribosylates lysine residues of the core histone tails

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S. Messner; M. Altmeyer; H. Zhao; A. Pozivil; B. Roschitzki; P. Gehrig; D. Rutishauser; D. Huang; A. Caflisch; M.O. Hottiger

Journal: Nucleic Acids Res.
Year: 2010
Volume: 38
Issue: 19
Pages: 6350-6362
DOI: 10.1093/nar/gkq463
Type of Publication: Journal Article

Acetylation; Adenosine Diphosphate Ribose; Catalytic Domain; Histones; Humans; Lysine; Models, Molecular; Poly(ADP-ribose) Polymerases


The chromatin-associated enzyme PARP1 has previously been suggested to ADP-ribosylate histones, but the specific ADP-ribose acceptor sites have remained enigmatic. Here, we show that PARP1 covalently ADP-ribosylates the amino-terminal histone tails of all core histones. Using biochemical tools and novel electron transfer dissociation mass spectrometric protocols, we identify for the first time K13 of H2A, K30 of H2B, K27 and K37 of H3, as well as K16 of H4 as ADP-ribose acceptor sites. Multiple explicit water molecular dynamics simulations of the H4 tail peptide into the catalytic cleft of PARP1 indicate that two stable intermolecular salt bridges hold the peptide in an orientation that allows K16 ADP-ribosylation. Consistent with a functional cross-talk between ADP-ribosylation and other histone tail modifications, acetylation of H4K16 inhibits ADP-ribosylation by PARP1. Taken together, our computational and experimental results provide strong evidence that PARP1 modifies important regulatory lysines of the core histone tails.