Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1.
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.
Berger
Felicitas
F
Institute of Biochemistry, Free University Berlin, 14195 Berlin, Germany.
Lau
Corinna
C
Ziegler
Mathias
M
D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000737:chemistry*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D012694:Serine / Q000737:chemistry
D051033:Apoptosis Inducing Factor; D020033:Protein Isoforms; D012694:Serine; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase