8ADJ

Poly(ADP-ribose) glycohydrolase (PARG) from Drosophila melanogaster in complex with PARG inhibitor PDD00017272

Summary for 8ADJ

• Entry DOI: 10.2210/pdb8adj/pdb
• Descriptor: Poly(ADP-ribose) glycohydrolase, 1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-(1-methylcyclopropyl)-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-bis(oxidanylidene)quinazoline-6-sulfonamide, GLYCEROL, ... (6 entities in total)
• Functional Keywords: parg, poly(adp-ribose) glycohydrolase, inhibitor, pdd00017272, hydrolase
• Biological source: Drosophila melanogaster (fruit fly)
• Total number of polymer chains: 3
• Total formula weight: 200667.99

Authors

Ariza, A.,Fontana, P. (deposition date: 2022-07-08, release date: 2023-06-14, Last modification date: 2024-02-07)

Primary citation

Fontana, P.,Buch-Larsen, S.C.,Suyari, O.,Smith, R.,Suskiewicz, M.J.,Schutzenhofer, K.,Ariza, A.,Rack, J.G.M.,Nielsen, M.L.,Ahel, I.
Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling.
Nat Commun, 14:3200-3200, 2023

PubMed Abstract: In the mammalian DNA damage response, ADP-ribosylation signalling is of crucial importance to mark sites of DNA damage as well as recruit and regulate repairs factors. Specifically, the PARP1:HPF1 complex recognises damaged DNA and catalyses the formation of serine-linked ADP-ribosylation marks (mono-Ser-ADPr), which are extended into ADP-ribose polymers (poly-Ser-ADPr) by PARP1 alone. Poly-Ser-ADPr is reversed by PARG, while the terminal mono-Ser-ADPr is removed by ARH3. Despite its significance and apparent evolutionary conservation, little is known about ADP-ribosylation signalling in non-mammalian Animalia. The presence of HPF1, but absence of ARH3, in some insect genomes, including Drosophila species, raises questions regarding the existence and reversal of serine-ADP-ribosylation in these species. Here we show by quantitative proteomics that Ser-ADPr is the major form of ADP-ribosylation in the DNA damage response of Drosophila melanogaster and is dependent on the dParp1:dHpf1 complex. Moreover, our structural and biochemical investigations uncover the mechanism of mono-Ser-ADPr removal by Drosophila Parg. Collectively, our data reveal PARP:HPF1-mediated Ser-ADPr as a defining feature of the DDR in Animalia. The striking conservation within this kingdom suggests that organisms that carry only a core set of ADP-ribosyl metabolising enzymes, such as Drosophila, are valuable model organisms to study the physiological role of Ser-ADPr signalling.

PubMed: 37268618
DOI: 10.1038/s41467-023-38793-y

Experimental method

X-RAY DIFFRACTION (2.508 Å)