Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins.

Elizaveta E Alemasova,Olga I Lavrik

doi:10.1093/nar/gkz120

Abstract

Poly(ADP-ribosyl)ation (PARylation) is posttranslational modification of proteins by linear or branched chains of ADP-ribose units, originating from NAD+. The central enzyme for PAR production in cells and the main target of poly(ADP-ribosyl)ation during DNA damage is poly(ADP-ribose) polymerase 1 (PARP1). PARP1 ability to function as a catalytic and acceptor protein simultaneously made a considerable contribution to accumulation of contradictory data. This topic is directly related to other questions, such as the stoichiometry of PARP1 molecules in auto-modification reaction, direction of the chain growth during PAR elongation and functional coupling of PARP1 with PARylation targets. Besides DNA damage necessary for the folding of catalytically active PARP1, other mechanisms appear to be required for the relevant intensity and specificity of PARylation reaction. Indeed, in recent years, PARP research has been enriched by the discovery of novel PARP1 interaction partners modulating its enzymatic activity. Understanding the details of PARP1 catalytic mechanism and its regulation is especially important in light of PARP-targeted therapy and may significantly aid to PARP inhibitors drug design. In this review we summarize old and up-to-date literature to clarify several points concerning PARylation mechanism and discuss different ways for regulation of PAR synthesis by accessory proteins reported thus far.

Highlights

Poly(ADP-ribosyl)ation (PARylation) is a special case of ADP-ribosylation––a phylogenetically ancient reaction of the transfer of ADP-ribose residues from NAD+ onto target substrates catalyzed by (ADP-ribosyl)transferases
The recent advances in the study of poly(ADP-ribosyl)ation are mainly concerned with the biological role and mode of operation of proteins belonging to the PARP family as well as with different functions of poly(ADP-ribosyl)ation in cells
The molecular mechanism of this process, which is important for understanding the part played by mono- and poly(ADP-ribosyl)ation in regulation of replication, transcription, DNA repair and protein stability/degradation remains unclear to a large extent

Summary

Introduction

Poly(ADP-ribosyl)ation (PARylation) is a special case of ADP-ribosylation––a phylogenetically ancient reaction of the transfer of ADP-ribose residues from NAD+ onto target substrates catalyzed by (ADP-ribosyl)transferases. Poly(ADP-ribosyl)ation reactions are widely used in eukaryotes, as PARP genes are absent in only a small number of eukaryotic species (1). PARP homologues apparently acquired through horizontal gene transfer can be found in bacteria (1). PARP from bacterium Herpetosiphon aurantiacus is activated by DNA like human PARP1 and can synthesize PAR polymers up to ∼15 units long (2). A protein with oligo(ADP-ribosyl)transferase activity was found in the archaeon (3). PARP genes probably gained from their hosts were identified in a number of dsDNA viruses (1)

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