Oncogenic role of HERC2 in familial glioma development: A review

Familial gliomas are rare primary brain tumors, accounting for around 5% of all glioma cases, and carry a strong familial predisposition, although their genetic basis remains incompletely understood. A recent 2023 Stanford study discovered that genome-wide sequencing has identified deleterious variants in HECT and RCC1-like domain-containing protein 2 (HERC2), the most significantly enriched gene in familial glioma cohorts. HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2), a large (~528 kDa) multifunctional E3 ubiquitin ligase, modulates DNA damage responses by catalyzing ubiquitin signaling cascades, facilitating the recruitment of repair proteins (breast cancer 1, p53-binding protein 1) through the ring finger protein 8/ubiquitin conjugating enzyme E2 13 complex, regulating p53 tetramerization through neuralized E3 ubiquitin protein ligase 4/E6-associated protein complexes, and controlling intra-S-phase checkpoint activation through the ubiquitin-specific peptidase 20-Claspin-checkpoint kinase 1 axis. Structurally, HERC2 comprises RCC1‐like domains for chromatin engagement, a mind bomb/HERC2 domain for E2 interactions, a CPH domain implicated in p53 stabilization, a ZZ‐type zinc finger, a DOC scaffold region, and a catalytic C-terminal HECT domain. Familial glioma-associated HERC2 mutations include missense variants and truncating loss-of-function alleles that impair ubiquitin-mediated coordination of normal protein degradation, induce TP53 dysfunction, and promote genomic instability. These findings highlight HERC2’s potential as a diagnostic biomarker and therapeutic target. Future studies are needed to determine the penetrance of HERC2 variants and assess their prognostic and predictive value in clinical practice.