The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1

Abstract The post-translational modification poly(ADP-ribosyl)ation (PARylation) plays key roles in genome maintenance and transcription. Both non-covalent poly(ADP-ribose) binding and covalent PARylation control protein functions, however, it is unknown how the two modes of modification crosstalk m...

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Published in:Nucleic acids research 2018-01, Vol.46 (2), p.804-822
Main Authors: Fischbach, Arthur, Krüger, Annika, Hampp, Stephanie, Assmann, Greta, Rank, Lisa, Hufnagel, Matthias, Stöckl, Martin T, Fischer, Jan M.F, Veith, Sebastian, Rossatti, Pascal, Ganz, Magdalena, Ferrando-May, Elisa, Hartwig, Andrea, Hauser, Karin, Wiesmüller, Lisa, Bürkle, Alexander, Mangerich, Aswin
Format: Article
Language:English
Subjects:
Molecular Biology
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Summary:Abstract The post-translational modification poly(ADP-ribosyl)ation (PARylation) plays key roles in genome maintenance and transcription. Both non-covalent poly(ADP-ribose) binding and covalent PARylation control protein functions, however, it is unknown how the two modes of modification crosstalk mechanistically. Employing the tumor suppressor p53 as a model substrate, this study provides detailed insights into the interplay between non-covalent and covalent PARylation and unravels its functional significance in the regulation of p53. We reveal that the multifunctional C-terminal domain (CTD) of p53 acts as the central hub in the PARylation-dependent regulation of p53. Specifically, p53 bound to auto-PARylated PARP1 via highly specific non-covalent PAR-CTD interaction, which conveyed target specificity for its covalent PARylation by PARP1. Strikingly, fusing the p53-CTD to a protein that is normally not PARylated, renders this a target for covalent PARylation as well. Functional studies revealed that the p53-PAR interaction had substantial implications on molecular and cellular levels. Thus, PAR significantly influenced the complex p53-DNA binding properties and controlled p53 functions, with major implications on the p53-dependent interactome, transcription, and replication-associated recombination. Remarkably, this mechanism potentially also applies to other PARylation targets, since a bioinformatics analysis revealed that CTD-like regions are highly enriched in the PARylated proteome.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx1205