HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity

• Published in: Molecular cell 2016-05, Vol.62 (3), p.432-442
• Main Authors: Gibbs-Seymour, Ian, Fontana, Pietro, Rack, Johannes Gregor Matthias, Ahel, Ivan
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate Ribose - metabolism; Antineoplastic Agents, Alkylating - pharmacology; Bone Neoplasms - drug therapy; Bone Neoplasms - enzymology; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; DNA; DNA Damage; DNA Repair - drug effects; Dose-Response Relationship, Drug; genome; HEK293 Cells; histones; Histones - genetics; Histones - metabolism; Humans; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Osteosarcoma - drug therapy; Osteosarcoma - enzymology; Osteosarcoma - genetics; Osteosarcoma - pathology; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein Binding; Protein Interaction Domains and Motifs; RNA Interference; Short; Transfection
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2016.03.008

We report the identification of histone PARylation factor 1 (HPF1; also known as C4orf27) as a regulator of ADP-ribosylation signaling in the DNA damage response. HPF1/C4orf27 forms a robust protein complex with PARP-1 in cells and is recruited to DNA lesions in a PARP-1-dependent manner, but independently of PARP-1 catalytic ADP-ribosylation activity. Functionally, HPF1 promotes PARP-1-dependent in trans ADP-ribosylation of histones and limits DNA damage-induced hyper-automodification of PARP-1. Human cells lacking HPF1 exhibit sensitivity to DNA damaging agents and PARP inhibition, thereby suggesting an important role for HPF1 in genome maintenance and regulating the efficacy of PARP inhibitors. Collectively, our results demonstrate how a fundamental step in PARP-1-dependent ADP-ribosylation signaling is regulated and suggest that HPF1 functions at the crossroads of histone ADP-ribosylation and PARP-1 automodification. [Display omitted] •Histone PARylation factor 1 (HPF1) is a component of the DNA damage response•HPF1 interacts with PARP-1 in cells via the PARP-1 catalytic domain•Loss of HPF1 sensitizes human cells to DNA damaging agents and PARP inhibition•HPF1 promotes PARP-1-dependent ADP-ribosylation of histones Gibbs-Seymour et al. identify histone PARylation factor 1 (HPF1; also known as C4orf27) as a PARP-1-interacting component of the DNA damage response. Deletion of HPF1 in human cells sensitizes cells to DNA damaging agents and to PARP inhibition. Functionally, HPF1 promotes PARP-1-dependent ADP-ribosylation of histones to ensure genome stability.