TY - JOUR

T1 - Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins

AU - Alemasova, Elizaveta E.

AU - Lavrik, Olga I.

N1 - Funding Information: Russian Scientific Fund [14-24-00038]; Russian State funded budget project [VI.57.1.2, 0309-2016-0001]. Funding for open access charge: Russian Scientific Fund [14-24-00038]. Conflict of interest statement. None declared. Publisher Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2019/5/7

Y1 - 2019/5/7

N2 - 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.

AB - 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.

KW - Adenosine Diphosphate Ribose/metabolism

KW - Animals

KW - Catalytic Domain

KW - DNA Damage

KW - DNA Repair

KW - DNA/chemistry

KW - Humans

KW - Isoenzymes/genetics

KW - Poly (ADP-Ribose) Polymerase-1/chemistry

KW - Poly ADP Ribosylation

KW - Poly Adenosine Diphosphate Ribose/biosynthesis

KW - Protein Binding

KW - Protein Folding

KW - Protein Multimerization

KW - Protein Processing, Post-Translational

UR - http://www.scopus.com/inward/record.url?scp=85065773561&partnerID=8YFLogxK

U2 - 10.1093/nar/gkz120

DO - 10.1093/nar/gkz120

M3 - Article

C2 - 30799503

AN - SCOPUS:85065773561

VL - 47

SP - 3811

EP - 3827

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 8

ER -