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

DOI: 10.1038/s41467-023-38793-y

Authors: Pietro Fontana (University of Oxford; Harvard Medical School; Boston Children’s Hospital) , Sara C. Buch-Larsen (University of Copenhagen) , Osamu Suyari (University of Oxford) , Rebecca Smith (University of Oxford) , Marcin J. Suskiewicz (University of Oxford) , Kira Schützenhofer (University of Oxford) , Antonio Ariza (University of Sheffield; University of Oxford) , Johannes Gregor Matthias Rack (University of Oxford) , Michael L. Nielsen (University of Copenhagen) , Ivan Ahel (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: June 2023
Diamond Proposal Number(s): 12346 , 18069

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.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 07/06/2023 09:15

Documents:
s41467-023-38793-y.pdf

Discipline Tags:

Genetics Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)