The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination

Abstract

A mutation in the HERC2 gene has been linked to a severe neurodevelopmental disorder with similarities to the Angelman syndrome. This gene codifies a protein with ubiquitin ligase activity that regulates the activity of tumor protein p53 and is involved in important cellular processes such as DNA repair, cell cycle, cancer, and iron metabolism. Despite the critical role of HERC2 in these physiological and pathological processes, little is known about its relevance in vivo. Here, we described a mouse with targeted inactivation of the Herc2 gene. Homozygous mice were not viable. Distinct from other ubiquitin ligases that interact with p53, such as MDM2 or MDM4, p53 depletion did not rescue the lethality of homozygous mice. The HERC2 protein levels were reduced by approximately one-half in heterozygous mice. Consequently, HERC2 activities, including ubiquitin ligase and stimulation of p53 activity, were lower in heterozygous mice. A decrease in HERC2 activities was also observed in human skin fibroblasts from individuals with an Angelman-like syndrome that express an unstable mutant protein of HERC2. Behavioural analysis of heterozygous mice identified an impaired motor synchronization with normal neuromuscular function. This effect was not observed in p53 knockout mice, indicating that a mechanism independent of p53 activity is involved. Morphological analysis showed the presence of HERC2 in Purkinje cells and a specific loss of these neurons in the cerebella of heterozygous mice. In these animals, an increase of autophagosomes and lysosomes was observed.Our findings establish a crucial role of HERC2 in embryonic development and motor coordination.

HERC2 Facilitates BLM and WRN Helicase Complex Interaction with RPA to Suppress G-Quadruplex DNA

“…HERC2 is a large HECT and RCC-like domain-containing protein comprising 4834 amino acids. Mutations in the HERC2 gene have been linked to a developmental delay (23,24), and mice with homozygous truncation of the gene are not viable (25). Although HERC2 performs a range of functions with various interacting proteins, one of its major roles is the regulation of DNA replication and damage response.…”

Peptidomic analysis of blastocyst culture medium and the effect of peptide derived from blastocyst culture medium on blastocyst formation and viability

“…Increased DNA repair and decreased sensitivity to apoptosis may have negative consequences on normal embryonic or fetal development (Mitchell, ). Cubillos‐Rojas et al () confirmed a new function for HERC2 ubiquitin ligase as a regulator of motor coordination, and this protein is essential for embryo growth. Although there are very few studies on the effects of HERC2 on human embryo development, the existing evidence suggests that HERC2 is a promising focus for future investigations.…”

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

“…Proteomic analysis implicated multiple molecular pathways in HERC2 mediated neurodevelopmental phenotype including pathways involved in the morphogenesis of neurons in addition to mitochondrial and ubiquitin-proteosome pathways (Abraham et al, 2019). Functional studies suggested a role for HERC2 protein in brain synaptogenesis and motor coordination (Cubillos-Rojas et al, 2016;Valnegri et al, 2017).…”