HERC1, encoding an E3 ubiquitin ligase, impacts cellular processes by regulating the ubiquitination of target proteins, such as C-RAF. It is involved in multiple pathways, including its role as a negative regulator of the mTOR pathway and as a guanine nucleotide exchange factor for ARF and Rab family GTPases [2,6]. Genetic models, like Herc1 -knockout mice, are valuable for studying its functions.

In Herc1 -knockout mice, depletion of HERC1 leads to imbalanced bone homeostasis presenting as osteopenia in both adult sexes, with only young female knockout mice showing increased osteoclast numbers and associated hormonal changes. HERC1 also regulates osteoblastogenesis and osteoclastogenesis [2]. In tambaleante (tbl) mice with a HERC1 mutation, there are losses in cerebellar Purkinje cells, synaptic vesicle deficits in the hippocampus, and anomalies in fiber projections, leading to phenotypes like cerebellar ataxia, motor coordination loss, and spatial deficits [1,5,7]. Additionally, HERC1 knockdown in breast cancer cell lines affects cell migration and invasion, and in AML models, loss of HERC1 enhances nucleoside analog-induced cell death by compromising cell cycle progression [3,4].

In conclusion, HERC1 plays essential roles in bone remodeling, neurobiology, and cancer-related processes. The study of Herc1-knockout or mutant mouse models has significantly contributed to understanding its functions in bone-related diseases, neurodevelopmental disorders, and cancer, providing potential therapeutic targets for these conditions.