Shulkina Alexandra, Hacker Kathrin, Ehrmann Julian F, Budroni Valentina, Mandlbauer Ariane, Bock Johannes, Grabarczyk Daniel B, Edobor Genevieve, Cochella Luisa, Clausen Tim, Versteeg Gijs A
Max Perutz Labs, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9, 1030, Vienna, Austria.
University of Vienna, Center for Molecular Biology, Department of Microbiology, Immunobiology and Genetics, Dr.-Bohr-Gasse 9, 1030, Vienna, Austria.
Nat Commun. 2025 Apr 24;16(1):3894. doi: 10.1038/s41467-025-59129-y.
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.
三联基序蛋白52（TRIM52）在人类中表现出强烈的正选择，但在许多其他哺乳动物中却缺失了。与对这种非保守因子的预期相反，TRIM52的缺失会损害细胞适应性。我们着手确定TRIM52的细胞功能。遗传和蛋白质组学分析表明，TRIM52在物理和功能上与DNA修复机制相互作用。我们的数据表明，TRIM52限制拓扑异构酶2加合物，从而防止细胞周期停滞。与促进适应性的功能一致，TRIM52在各种癌症中上调，促使我们研究其调控途径。我们发现TRIM52被巨型E3泛素连接酶BIRC6、HUWE1和UBR4/KCMF1靶向进行超快速蛋白酶体降解。BIRC6将TRIM52单泛素化，随后由UBR4/KCMF1进行延伸。这些发现表明TRIM52在维持基因组完整性以及通过多连接酶降解调节自身丰度方面发挥作用。
