Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nucleic acids research, 2018-01, Vol.46 (2), p.804

Ort / Verlag

England

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.