TRIM52 maintains cellular fitness and is under tight proteolytic control by multiple giant E3 ligases

Alexandra Shulkina, Kathrin Hacker, Julian F. Ehrmann, Valentina Budroni, Ariane Mandlbauer, Johannes Bock, Daniel B. Grabarczyk, Genevieve Edobor, Luisa Cochella, Tim Clausen and Gijs A. Versteeg ()
Additional contact information
Alexandra Shulkina: Dr.-Bohr-Gasse 9
Kathrin Hacker: Dr.-Bohr-Gasse 9
Julian F. Ehrmann: a Doctoral School of the University of Vienna and the Medical University of Vienna
Valentina Budroni: Dr.-Bohr-Gasse 9
Ariane Mandlbauer: Johns Hopkins School of Medicine
Johannes Bock: Dr.-Bohr-Gasse 9
Daniel B. Grabarczyk: Vienna BioCenter (VBC)
Genevieve Edobor: Dr.-Bohr-Gasse 9
Luisa Cochella: Johns Hopkins School of Medicine
Tim Clausen: Vienna BioCenter (VBC)
Gijs A. Versteeg: Dr.-Bohr-Gasse 9

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Tripartite motif 52 (TRIM52) exhibits strong positive selection in humans, yet is lost in many other mammals. In contrast to what one would expect for such a non-conserved factor, TRIM52 loss compromises cell fitness. We set out to determine the cellular function of TRIM52. Genetic and proteomic analyses revealed TRIM52 physically and functionally interacts with the DNA repair machinery. Our data suggest that TRIM52 limits topoisomerase 2 adducts, thereby preventing cell-cycle arrest. Consistent with a fitness-promoting function, TRIM52 is upregulated in various cancers, prompting us to investigate its regulatory pathways. We found TRIM52 to be targeted for ultra-rapid proteasomal degradation by the giant E3 ubiquitin ligases BIRC6, HUWE1, and UBR4/KCMF1. BIRC6 mono-ubiquitinates TRIM52, with subsequent extension by UBR4/KCMF1. These findings suggest a role for TRIM52 in maintaining genome integrity, and regulation of its own abundance through multi-ligase degradation.

Date: 2025
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DOI: 10.1038/s41467-025-59129-y

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