Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

Mark S. Dunstan, Eva Barkauskaite, Pierre Lafite, Claire Knezevic, Amy Brassington, Marijan Ahel, Paul J. Hergenrother, David Leys, Ivan Ahel

Research output: Contribution to journalArticle

Abstract

Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.

Original languageEnglish (US)
Article number878
JournalNature Communications
Volume3
DOIs
StatePublished - Jul 6 2012
Externally publishedYes

Fingerprint

ribose
adenosine diphosphate
Glycoside Hydrolases
inhibitors
Tetrahymena thermophila
mitosis
chromatin
Ribose
apoptosis
Adenosine Diphosphate
Rhodanine
deoxyribonucleic acid
activation
proteins
Poly Adenosine Diphosphate Ribose
Post Translational Protein Processing
Mitosis
DNA Repair
Transcriptional Activation
Chromatin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Dunstan, M. S., Barkauskaite, E., Lafite, P., Knezevic, C., Brassington, A., Ahel, M., ... Ahel, I. (2012). Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase. Nature Communications, 3, [878]. https://doi.org/10.1038/ncomms1889

Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase. / Dunstan, Mark S.; Barkauskaite, Eva; Lafite, Pierre; Knezevic, Claire; Brassington, Amy; Ahel, Marijan; Hergenrother, Paul J.; Leys, David; Ahel, Ivan.

In: Nature Communications, Vol. 3, 878, 06.07.2012.

Research output: Contribution to journalArticle

Dunstan, MS, Barkauskaite, E, Lafite, P, Knezevic, C, Brassington, A, Ahel, M, Hergenrother, PJ, Leys, D & Ahel, I 2012, 'Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase', Nature Communications, vol. 3, 878. https://doi.org/10.1038/ncomms1889
Dunstan, Mark S. ; Barkauskaite, Eva ; Lafite, Pierre ; Knezevic, Claire ; Brassington, Amy ; Ahel, Marijan ; Hergenrother, Paul J. ; Leys, David ; Ahel, Ivan. / Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase. In: Nature Communications. 2012 ; Vol. 3.
@article{a6054bd3fd0e470f9b952ee20429c327,
title = "Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase",
abstract = "Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€{"}ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.",
author = "Dunstan, {Mark S.} and Eva Barkauskaite and Pierre Lafite and Claire Knezevic and Amy Brassington and Marijan Ahel and Hergenrother, {Paul J.} and David Leys and Ivan Ahel",
year = "2012",
month = "7",
day = "6",
doi = "10.1038/ncomms1889",
language = "English (US)",
volume = "3",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

AU - Dunstan, Mark S.

AU - Barkauskaite, Eva

AU - Lafite, Pierre

AU - Knezevic, Claire

AU - Brassington, Amy

AU - Ahel, Marijan

AU - Hergenrother, Paul J.

AU - Leys, David

AU - Ahel, Ivan

PY - 2012/7/6

Y1 - 2012/7/6

N2 - Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.

AB - Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=84863313761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863313761&partnerID=8YFLogxK

U2 - 10.1038/ncomms1889

DO - 10.1038/ncomms1889

M3 - Article

C2 - 22673905

AN - SCOPUS:84863313761

VL - 3

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 878

ER -