Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 10; pp. 3765 - 3770
• Main Authors: Berger, Felicitas, Lau, Corinna, Ziegler, Mathias
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.03.2007; National Acad Sciences
• Subjects: Adenosine diphosphate; Amino acids; Apoptosis; Apoptosis Inducing Factor - metabolism; aspartic acid; Autoradiography; Biochemistry; Biological Sciences; Biosynthesis; Catalytic activity; Cell Nucleus - metabolism; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA damage; Enzymes; Fibroblasts - metabolism; Gene expression regulation; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Metabolism; mitochondria; NAD (coenzyme); NAD ADP-ribosyltransferase; Nicotinamide-Nucleotide Adenylyltransferase - chemistry; Phosphates; Phosphorylation; Poly(ADP-ribose) Polymerases - biosynthesis; Poly(ADP-ribose) Polymerases - genetics; Protein Isoforms; protein kinase C; Protein Kinase C - metabolism; protein phosphorylation; Protein Transport; Proteins; Relocation; serine; Serine - chemistry; signal transduction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0609211104

Nuclear NAD⁺ metabolism constitutes a major component of signaling pathways. It includes NAD⁺-dependent protein deacetylation by members of the Sir2 family and protein modification by poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 has emerged as an important mediator of processes involving DNA rearrangements. High-affinity binding to breaks in DNA activates PARP-1, which attaches poly(ADP-ribose) (PAR) to target proteins. NMN adenylyl transferases (NMNATs) catalyze the final step of NAD⁺ biosynthesis. We report here that the nuclear isoform NMNAT-1 stimulates PARP-1 activity and binds to PAR. Its overexpression in HeLa cells promotes the relocation of apoptosis-inducing factor from the mitochondria to the nucleus, a process known to depend on poly(ADP-ribosyl)ation. Moreover, NMNAT-1 is subject to phosphorylation by protein kinase C, resulting in reduced binding to PAR. Mimicking phosphorylation, substitution of the target serine residue by aspartate precludes PAR binding and stimulation of PARP-1. We conclude that, depending on its state of phosphorylation, NMNAT-1 binds to activated, automodifying PARP-1 and thereby amplifies poly(ADP-ribosyl)ation.