Gene expression signature predicts rate of type 1 diabetes progression

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  • Tomi Suomi
  • Inna Starskaia
  • Ubaid Ullah Kalim
  • Omid Rasool
  • Maria K. Jaakkola
  • Toni Grönroos
  • Tommi Välikangas
  • Caroline Brorsson
  • Gianluca Mazzoni
  • Sylvaine Bruggraber
  • Lutgart Overbergh
  • David Dunger
  • Mark Peakman
  • Chmura, Piotr Jaroslaw
  • Brunak, Søren
  • Anke M. Schulte
  • Chantal Mathieu
  • Mikael Knip
  • Riitta Lahesmaa
  • Laura L. Elo
  • Pociot, Flemming (Medlem af forfattergruppering)
  • Johannesen, Jesper (Medlem af forfattergruppering)
  • Rossing, Peter (Medlem af forfattergruppering)
  • INNODIA consortium
In the mammalian DNA damage response, ADP-ribosylation signalling is of
crucial importance tomark 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 ADPribosylation
in the DNA damage response of Drosophila melanogaster and is
dependent on the dParp1:dHpf1 complex. Moreover, our structural and biochemical
investigations uncover themechanism ofmono-Ser-ADPr removal by
Drosophila Parg. Collectively, our data reveal PARP:HPF1-mediated Ser-ADPr as
adefining 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.
OriginalsprogEngelsk
Artikelnummer104625
TidsskriftEBioMedicine
Vol/bind92
Antal sider18
ISSN2352-3964
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
Funding: R.L. received funding from the Academy of Finland (grants 292335 , 294337 , 319280 , 31444 , 319280 , 329277 , 331790 ), Business Finland and by grants from the JDRF, the Sigrid Jusélius Foundation (SJF), Jane and Aatos Erkko Foundation , Finnish Diabetes Foundation and the Finnish Cancer Foundation . R.L. and M.K. were supported by the Academy of Finland , AoF, Centre of Excellence in Molecular Systems Immunology and Physiology Research (2012–2017) grant 250114 and grant 292482. I.S. was supported by Turku Doctoral Programme of Molecular Medicine (TuDMM) and Finnish Diabetes Research Foundation . Prof. Elo reports grants from the European Research Council ERC ( 677943 ), Academy of Finland ( 310561 , 314443 , 329278 , 335434 , 335611 and 341342 ), and Sigrid Jusélius Foundation during the conduct of the study.

Funding Information:
Our research is also supported by University of Turku Graduate School (UTUGS), Biocenter Finland , ELIXIR Finland, and by InFLAMES Flagship Programme of the Academy of Finland (decision number: 337530).

Funding Information:
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA) and No 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union's Horizon 2020 research and innovation programme , ‘EFPIA’, ‘JDRF’ and ‘The Leona M. and Harry B. Helmsley Charitable Trust’.

Publisher Copyright:
© 2023 The Authors

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