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REVIEW ARTICLE

Oncogenic role of HERC2 in familial glioma development: A review

Michael Christian A. Virata1* ,  Jasmine Soco Interior2 ,  Patrick Reyes Relacion3,4 ,  Ryan Gabriel C. Molen5
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1 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, New York, United States of America
2 Department of Biochemistry, Biological Foundations of Medicine, School of Medicine, Mapúa University, Makati, Metro Manila, Philippines
3 College of Allied Health Professions, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Metro Manila, Philippines
4 College of Public Health, University of the Philippines, Manila, Philippines
5 School of Medicine and Public Health, Ateneo de Manila University, Ortigas, Pasig City, Philippines
Advanced Neurology, 025220069 https://doi.org/10.36922/AN025220069
Received: 30 May 2025 | Revised: 7 July 2025 | Accepted: 18 July 2025 | Published online: 29 July 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

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.

Keywords
Brain tumor
HECT and RCC1-like domain-containing protein 2
Familial glioma
Ubiquitin signaling
TP53
Genomic instability
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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