Poly(ADP-ribosyl)ation by PARP1: Reaction Mechanism and Regulatory Proteins

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2019 Feb 26

PMID 30799503

Citations 198

Authors

Elizaveta E Alemasova

Olga I Lavrik

Affiliations

Soon will be listed here.

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.

Citing Articles

PARP2 Catalytic Activity Is Allosterically Stimulated by Binding to the c-KIT1 G-Quadruplex.

Singh Hanuman D, Neeharika S, Rajakumara E ACS Omega. 2025; 10(8):8767-8776.

PMID: 40060879 PMC: 11886757. DOI: 10.1021/acsomega.5c00724.

XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.

Lin X, Leung K, Wolfe K, Call N, Bhandari S, Huang X Nucleic Acids Res. 2025; 53(4).

PMID: 39970298 PMC: 11838041. DOI: 10.1093/nar/gkaf086.

Multi-stage structure-based virtual screening approach combining 3D pharmacophore, docking and molecular dynamic simulation towards the identification of potential selective PARP-1 inhibitors.

El Hassab M, Eldehna W, Hassan G, Abou-Seri S BMC Chem. 2025; 19(1):30.

PMID: 39893479 PMC: 11786381. DOI: 10.1186/s13065-025-01389-2.

Single-molecule analysis of PARP1-G-quadruplex interaction.

Gaur P, Bain F, Meah R, Spies M bioRxiv. 2025; .

PMID: 39829912 PMC: 11741300. DOI: 10.1101/2025.01.06.631587.

Proteins Associated with Neurodegenerative Diseases: Link to DNA Repair.

Khodyreva S, Dyrkheeva N, Lavrik O Biomedicines. 2025; 12(12.

PMID: 39767715 PMC: 11673744. DOI: 10.3390/biomedicines12122808.

References

Naegeli H, Loetscher P, Althaus F . Poly ADP-ribosylation of proteins. Processivity of a post-translational modification. J Biol Chem. 1989; 264(24):14382-5. View

Larsen S, Hendriks I, Lyon D, Jensen L, Nielsen M . Systems-wide Analysis of Serine ADP-Ribosylation Reveals Widespread Occurrence and Site-Specific Overlap with Phosphorylation. Cell Rep. 2018; 24(9):2493-2505.e4. DOI: 10.1016/j.celrep.2018.07.083. View

Sukhanova M, Abrakhi S, Joshi V, Pastre D, Kutuzov M, Anarbaev R . Single molecule detection of PARP1 and PARP2 interaction with DNA strand breaks and their poly(ADP-ribosyl)ation using high-resolution AFM imaging. Nucleic Acids Res. 2015; 44(6):e60. PMC: 4824093. DOI: 10.1093/nar/gkv1476. View

DAmours D, Desnoyers S, DSilva I, Poirier G . Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J. 1999; 342 ( Pt 2):249-68. PMC: 1220459. View

Perina D, Mikoc A, Ahel J, Cetkovic H, Zaja R, Ahel I . Distribution of protein poly(ADP-ribosyl)ation systems across all domains of life. DNA Repair (Amst). 2014; 23:4-16. PMC: 4245714. DOI: 10.1016/j.dnarep.2014.05.003. View

. 3'-Deoxy-NAD+ as a substrate for poly(ADP-ribose)polymerase and the reaction mechanism of poly(ADP-ribose) elongation. J Biol Chem. 1988; 263(33):17690-6. View

Kretov D, Curmi P, Hamon L, Abrakhi S, Desforges B, Ovchinnikov L . mRNA and DNA selection via protein multimerization: YB-1 as a case study. Nucleic Acids Res. 2015; 43(19):9457-73. PMC: 4627072. DOI: 10.1093/nar/gkv822. View

Masaoka A, Gassman N, Kedar P, Prasad R, Hou E, Horton J . HMGN1 protein regulates poly(ADP-ribose) polymerase-1 (PARP-1) self-PARylation in mouse fibroblasts. J Biol Chem. 2012; 287(33):27648-58. PMC: 3431713. DOI: 10.1074/jbc.M112.370759. View

Gibson B, Kraus W . New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012; 13(7):411-24. DOI: 10.1038/nrm3376. View

10.

Tao Z, Gao P, Hoffman D, Liu H . Domain C of human poly(ADP-ribose) polymerase-1 is important for enzyme activity and contains a novel zinc-ribbon motif. Biochemistry. 2008; 47(21):5804-13. DOI: 10.1021/bi800018a. View

11.

Rulten S, Fisher A, Robert I, Zuma M, Rouleau M, Ju L . PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol Cell. 2011; 41(1):33-45. DOI: 10.1016/j.molcel.2010.12.006. View

12.

Bock F, Todorova T, Chang P . RNA Regulation by Poly(ADP-Ribose) Polymerases. Mol Cell. 2015; 58(6):959-69. PMC: 4475274. DOI: 10.1016/j.molcel.2015.01.037. View

13.

Loseva O, Jemth A, Bryant H, Schuler H, Lehtio L, Karlberg T . PARP-3 is a mono-ADP-ribosylase that activates PARP-1 in the absence of DNA. J Biol Chem. 2010; 285(11):8054-60. PMC: 2832956. DOI: 10.1074/jbc.M109.077834. View

14.

Ouararhni K, Hadj-Slimane R, Ait-Si-Ali S, Robin P, Mietton F, Harel-Bellan A . The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 2006; 20(23):3324-36. PMC: 1686608. DOI: 10.1101/gad.396106. View

15.

Rolli V, OFarrell M, de Murcia G . Random mutagenesis of the poly(ADP-ribose) polymerase catalytic domain reveals amino acids involved in polymer branching. Biochemistry. 1997; 36(40):12147-54. DOI: 10.1021/bi971055p. View

16.

Hottiger M . Nuclear ADP-Ribosylation and Its Role in Chromatin Plasticity, Cell Differentiation, and Epigenetics. Annu Rev Biochem. 2015; 84:227-63. DOI: 10.1146/annurev-biochem-060614-034506. View

17.

Dawicki-McKenna J, Langelier M, DeNizio J, Riccio A, Cao C, Karch K . PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. Mol Cell. 2015; 60(5):755-768. PMC: 4712911. DOI: 10.1016/j.molcel.2015.10.013. View

18.

Daniels C, Ong S, Leung A . Phosphoproteomic approach to characterize protein mono- and poly(ADP-ribosyl)ation sites from cells. J Proteome Res. 2014; 13(8):3510-22. PMC: 4123941. DOI: 10.1021/pr401032q. View

19.

Murai J, Huang S, Das B, Renaud A, Zhang Y, Doroshow J . Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012; 72(21):5588-99. PMC: 3528345. DOI: 10.1158/0008-5472.CAN-12-2753. View

20.

Marsischky G, Wilson B, Collier R . Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. J Biol Chem. 1995; 270(7):3247-54. DOI: 10.1074/jbc.270.7.3247. View