TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases

Shulkina, A.; Hacker, K.; Ehrmann, J. F.; Budroni, V.; Mandlbauer, A.; Bock, J.; Grabarczyk, D. B.; Cochella, L.; Clausen, T.; Versteeg, G. A.

doi:10.1101/2024.05.16.594269

bioRxiv · 10.1101/2024.05.16.594269

TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases

Shulkina, A.·Hacker, K.·Ehrmann, J. F.·Budroni, V.·Mandlbauer, A.·Bock, J.·Grabarczyk, D. B.·Cochella, L.·Clausen, T.·Versteeg, G. A.

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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 TRIM52s involvement in resolving topoisomerase 2 (TOP2)-DNA cross-links, mitigating DNA damage and 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 underscore TRIM52s pivotal role in DNA damage repair and regulation of its own abundance through multi-ligase degradation.

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Shulkina, A., Hacker, K., Ehrmann, J. F., Budroni, V., Mandlbauer, A., Bock, J., Grabarczyk, D. B., Cochella, L., Clausen, T., Versteeg, G. A.. 2024-05-16. TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases. https://doi.org/10.1101/2024.05.16.594269

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