Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling

Pietro Fontana, Sara C. Buch-Larsen, Osamu Suyari, Rebecca Smith, Marcin J. Suskiewicz, Kira Schützenhofer, Antonio Ariza (), Johannes Gregor Matthias Rack (), Michael L. Nielsen () and Ivan Ahel ()
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Pietro Fontana: University of Oxford, South Parks Road
Sara C. Buch-Larsen: University of Copenhagen, Blegdamsvej 3B
Osamu Suyari: University of Oxford, South Parks Road
Rebecca Smith: University of Oxford, South Parks Road
Marcin J. Suskiewicz: University of Oxford, South Parks Road
Kira Schützenhofer: University of Oxford, South Parks Road
Antonio Ariza: University of Oxford, South Parks Road
Johannes Gregor Matthias Rack: University of Oxford, South Parks Road
Michael L. Nielsen: University of Copenhagen, Blegdamsvej 3B
Ivan Ahel: University of Oxford, South Parks Road

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38793-y

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