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| Item Type: | Article |
|---|---|
| Title: | Functional landscape of ubiquitin linkages couples K29-linked ubiquitylation to epigenome integrity |
| Creators: |
Arroyo-Gomez, Javier  ORCID: https://orcid.org/0009-0003-7751-1853, Murray, Matthew J. ORCID: https://orcid.org/0000-0002-0379-7161, Guérillon, Claire ORCID: https://orcid.org/0000-0002-1982-6596, Wang, Juanjuan, Isaakova, Ekaterina, Reverón-Gómez, Nazaret ORCID: https://orcid.org/0000-0001-7347-781X, Koutrouli, Mikaela, Suryo Rahmanto, Aldwin, Mitrofanov, Katrine ORCID: https://orcid.org/0009-0009-2181-5552, Ingham, Andreas, Schovsbo, Sofie, Weischenfeldt, Katrine, Coscia, Fabian ORCID: https://orcid.org/0000-0002-2244-5081, Typas, Dimitris, Völker-Albert, Moritz, Solis, Victor, Jensen, Lars Juhl ORCID: https://orcid.org/0000-0001-7885-715X, Groth, Anja, Mund, Andreas ORCID: https://orcid.org/0000-0002-7843-5341, Beli, Petra, Shearer, Robert F. ORCID: https://orcid.org/0000-0003-3012-8788 and Mailand, Niels ORCID: https://orcid.org/0000-0002-6623-709X
|
| Abstract: | 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 CullinRING 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. |
| Keywords: | Ubiquitin, Linkage-Specific Ubiquitylation, Ubiquitin-Dependent proteolysis, Epigenome Maintenance, Heterochromatin |
| Source: | EMBO Journal |
| ISSN: | 0261-4189 |
| Publisher: | EMBO Press |
| Volume: | 44 |
| Number: | 23 |
| Page Range: | 6944-6978 |
| Date: | December 2025 |
| Official Publication: | https://doi.org/10.1038/s44318-025-00599-7 |
| PubMed: | View item in PubMed |
| Related to: |
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