Profiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1

Camilla S. Colding-Christensen, Ellen S. Kakulidis, Javier Arroyo-Gomez, Ivo A. Hendriks, Connor Arkinson, Zita Fábián, Agnieszka Gambus, Niels Mailand, Julien P. Duxin () and Michael L. Nielsen ()
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Camilla S. Colding-Christensen: University of Copenhagen
Ellen S. Kakulidis: University of Copenhagen
Javier Arroyo-Gomez: University of Copenhagen
Ivo A. Hendriks: University of Copenhagen
Connor Arkinson: University of Birmingham
Zita Fábián: University of Copenhagen
Agnieszka Gambus: University of Birmingham
Niels Mailand: University of Copenhagen
Julien P. Duxin: University of Copenhagen
Michael L. Nielsen: University of Copenhagen

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Ubiquitin widely modifies proteins, thereby regulating most cellular functions. The complexity of ubiquitin signalling necessitates unbiased methods enabling global detection of dynamic protein ubiquitylation. Here, we describe UBIMAX (UBiquitin target Identification by Mass spectrometry in Xenopus egg extracts), which enriches ubiquitin-conjugated proteins and quantifies regulation of protein ubiquitylation under precise and adaptable conditions. We benchmark UBIMAX by investigating DNA double-strand break-responsive ubiquitylation events, identifying previously known targets and revealing the actin-organizing protein Dbn1 as a major target of DNA damage-induced ubiquitylation. We find that Dbn1 is targeted for proteasomal degradation by the SCFβ-Trcp1 ubiquitin ligase, in a conserved mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-Trcp1 degron containing an SQ motif. We further show that this degron is sufficient to induce DNA damage-dependent protein degradation of a model substrate. Collectively, we demonstrate UBIMAX’s ability to identify targets of stimulus-regulated ubiquitylation and reveal an SCFβ-Trcp1-mediated ubiquitylation mechanism controlled directly by the apical DNA damage response kinases.

Date: 2023
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DOI: 10.1038/s41467-023-43873-0

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