Family-wide analysis of poly(ADP-ribose) polymerase activity

• Published in: Nature communications Vol. 5; no. 1; p. 4426
• Main Authors: Vyas, Sejal, Matic, Ivan, Uchima, Lilen, Rood, Jenny, Zaja, Roko, Hay, Ronald T., Ahel, Ivan, Chang, Paul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2014; Nature Publishing Group
• Subjects: 38; 38/109; 631/45/173; 631/80/458/2389; 82; 82/16; 82/29; 82/80; 82/83; Adenosine Diphosphate Ribose - metabolism; Amino Acid Motifs; Cells, Cultured; Cysteine - metabolism; Humanities and Social Sciences; Humans; Lysine - metabolism; multidisciplinary; Poly Adenosine Diphosphate Ribose - metabolism; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5426

The poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) protein family generates ADP-ribose (ADPr) modifications onto target proteins using NAD + as substrate. Based on the composition of three NAD + coordinating amino acids, the H-Y-E motif, each PARP is predicted to generate either poly(ADPr) (PAR) or mono(ADPr) (MAR). However, the reaction product of each PARP has not been clearly defined, and is an important priority since PAR and MAR function via distinct mechanisms. Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. We identify automodification sites on seven PARPs, and demonstrate that MAR and PAR generating PARPs modify similar amino acids, suggesting that the sequence and structural constraints limiting PARPs to MAR synthesis do not limit their ability to modify canonical amino-acid targets. In addition, we identify cysteine as a novel amino-acid target for ADP-ribosylation on PARPs. The poly(ADP-ribose) polymerase family of enzymes control many aspects of cellular signalling by covalently modifying proteins with either poly- or mono-(ADP-ribose). Vyas et al. catalogue the catalytic specificity of this family, and reveal that the majority of these enzymes generate only mono(ADP-ribose).