Evidence is mounting that crosstalk between ubiquitylation and ADP-ribosylation is crucial for maintaining proteostasis. Recent studies have revealed that mono(ADP-ribose) can recruit and activate specific ubiquitin E3 ligases. In this Comment, we discuss MARUbylation — the (literal) linking of mono(ADP-ribose) and ubiquitin into a distinct new hybrid modification.
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References
Swatek, K. N. & Komander, D. Ubiquitin modifications. Cell Res. 26, 399–422 (2016).
Cohen, M. S. & Chang, P. Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat. Chem. Bio.l 14, 236–243 (2018).
Dikic, I. & Schulman, B. A. An expanded lexicon for the ubiquitin code. Nat. Rev. Mol. Cell Biol. 24, 273–287 (2023).
Zhang, Y. et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat. Cell Biol. 13, 623–629 (2011).
Perrard, J. & Smith, S. Multiple E3 ligases control tankyrase stability and function. Nat. Commun. 14, 7208 (2023).
DaRosa, P. A. et al. Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal. Nature 517, 223–226 (2015).
Yang, C. S. et al. Ubiquitin Modification by the E3 Ligase/ADP-ribosyltransferase Dtx3L/Parp9. Mol. Cell 66, 503–516 (2017).
Zhu, K. et al. DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on protein substrates. Sci. Adv. 8, eadd4253 (2022).
Bejan, D. S., Lacoursiere, R. E., Pruneda, J. N. & Cohen, M. S. Ubiquitin is directly linked via an ester to protein-conjugated mono-ADP-ribose. EMBO J. 44, 2211–2231 (2025).
Kolvenbach, A. et al. Serine ADPr on histones and PARP1 is a cellular target of ester-linked ubiquitylation. Nat. Chem. Biol. https://doi.org/10.1038/s41589-025-01974-5 (2025).
Perrard, J., Gao, K., Ring, K. & Smith, S. Deltex and RING-UIM E3 ligases cooperate to create a ubiquitin-ADP-ribose hybrid mark on tankyrase, promoting its stabilization. Sci. Adv. 5, eadx7172 (2025).
Lacoursiere, R. E. et al. A family of E3 ligases extend K11 polyubiquitin on sites of MARUbylation. Preprint at bioRxiv https://doi.org/10.1101/2025.05.11.653360 (2025).
Kloet, M. S. et al. Identification of RNF114 as ADPr-Ub reader through non-hydrolysable ubiquitinated ADP-ribose. Nat. Commun. 16, 6319 (2025).
Longarini, E. J. et al. Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling. Mol. Cell 83, 1743–1760 (2023).
Acknowledgements
This work was supported by the US National Institute of Neurological Disorders and Stroke (2R01NS088629 to M.S.C.) and by the US National Institute of General Medical Sciences (R35GM142486 to J.N.P.).
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Pruneda, J.N., Žaja, R., Cohen, M.S. et al. The emergence of MARUbe — a hybrid ADP-ribose–ubiquitin modification. Nat Rev Mol Cell Biol 26, 820–821 (2025). https://doi.org/10.1038/s41580-025-00903-7
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DOI: https://doi.org/10.1038/s41580-025-00903-7
