Functional landscape of ubiquitin linkages couples K29-linked ubiquitylation to epigenome integrity
Linkage-specific ubiquitin chains govern the outcome of numerous critical ubiquitin-dependent signaling processes, but their targets and functional impacts remain incompletely understood due to a paucity of tools for their specific detection and manipulation. Here, we applied a cell-based ubiquitin replacement strategy enabling targeted conditional abrogation of each of the seven lysine-based ubiquitin linkages in human cells to profile system-wide impacts of disabling formation of individual chain types. This revealed proteins and processes regulated by each of these poly-ubiquitin topologies and indispensable roles of K48-, K63- and K27-linkages in cell proliferation. We show that K29-linked ubiquitylation is strongly associated with chromosome biology, and that the H3K9me3 methyltransferase SUV39H1 is a prominent cellular target of this modification. K29-linked ubiquitylation catalyzed by TRIP12 and reversed by TRABID constitutes the essential degradation signal for SUV39H1 and is primed and extended by Cullin-RING ubiquitin ligase activity. Preventing K29-linkage-dependent SUV39H1 turnover deregulates H3K9me3 homeostasis but not other histone modifications. Collectively, these data resources illuminate cellular functions of linkage-specific ubiquitin chains and establish a key role of K29-linked ubiquitylation in epigenome integrity.
Authors
- Victor Solis
- Lars Juhl Jensen (ORCID: https://orcid.org/0000-0001-7885-715X)
- Petra Beli (ORCID: https://orcid.org/0000-0001-9507-9820)
- Nazaret Reverón-Gómez (ORCID: https://orcid.org/0000-0001-7347-781X)
- Aldwin Suryo Rahmanto (ORCID: https://orcid.org/0000-0002-4593-286X)
- Matthew J Murray (ORCID: https://orcid.org/0000-0002-0379-7161)
- Sofie Schovsbo (ORCID: https://orcid.org/0000-0002-7173-0911)
- Robert F. Shearer (ORCID: https://orcid.org/0000-0003-3012-8788)
- Andreas Ingham (ORCID: https://orcid.org/0000-0003-4843-9285)
- Dimitris Typas (ORCID: https://orcid.org/0000-0002-8737-1319)
- Andreas Mund (ORCID: https://orcid.org/0000-0002-7843-5341)
- Claire Guérillon (ORCID: https://orcid.org/0000-0002-1982-6596)
- Mikaela Koutrouli (ORCID: https://orcid.org/0000-0002-8953-3561)
- Niels Mailand (ORCID: https://orcid.org/0000-0002-6623-709X)
- Anja Groth (ORCID: https://orcid.org/0000-0003-0577-1771)
- Ekaterina Isaakova
- Fabian Coscia (ORCID: https://orcid.org/0000-0002-2244-5081)
- Moritz Völker-Albert (ORCID: https://orcid.org/0009-0003-2946-1169)
- Javier Arroyo-Gomez (ORCID: https://orcid.org/0009-0003-7751-1853)
- Juanjuan Wang (ORCID: https://orcid.org/0000-0002-1692-7455)
- Konstantin Y. Mitrofanov
- Katrine Weischenfeldt
Institutions
- Max Delbrück Center (DE)
- Novo Nordisk Foundation (DK)
- Danish Cancer Society (DK)
- Urologische Klinik München (DE)
- Institute of Molecular Biology (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1038/s44318-025-00599-7
- Citations
- 2
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- European Commission
- National Research Foundation
- Danmarks Grundforskningsfond
- Lundbeckfonden
- Novo Nordisk
- Novo Nordisk Fonden
- H. Lundbeck A/S