8adk | pdb_00008adk
Poly(ADP-ribose) glycohydrolase (PARG) from Drosophila melanogaster
Structural highlights
FunctionPARG_DROME Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. Poly(ADP-ribose) metabolism is required for maintenance of the normal function of neuronal cells.[1] Publication Abstract from PubMedIn 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. Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling.,Fontana P, Buch-Larsen SC, Suyari O, Smith R, Suskiewicz MJ, Schutzenhofer K, Ariza A, Rack JGM, Nielsen ML, Ahel I Nat Commun. 2023 Jun 2;14(1):3200. doi: 10.1038/s41467-023-38793-y. PMID:37268618[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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