HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2)

HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2) is a giant, multifunctional E3 ubiquitin ligase of the large HERC family, characterized by the presence of a C-terminal "homologous to E6AP carboxyl terminus" (HECT) domain and multiple RCC1-like (RLD) domains[1][5][7]. HERC2 plays a major role in ubiquitination, marking specific proteins for proteasomal degradation. Key substrates and pathways regulated by HERC2 include DNA repair proteins (e.g., BRCA1, XPA), cell cycle proteins, and the iron homeostasis regulator FBXL5[1][2][5][6][7].\nHERC2 functions in pivotal cellular and physiological processes such as DNA damage response—facilitating protein recruitment to damaged chromatin, controlling the activity of p53 by promoting its oligomerization and transcriptional activation, and modulating circadian oscillation of nucleotide excision repair[1][3][6][7]. It also regulates iron metabolism, centrosome stability, intracellular trafficking, and pigmentation through OCA2 gene regulation[2][5][7].\nGenetic variants in HERC2 are linked to human eye and skin color variation as well as increased skin cancer risk; disruptions or mutations in HERC2 are implicated in cancer, neurodevelopmental/neurodegenerative diseases, and other complex disorders, reflecting its broad physiological roles and importance in maintaining cellular homeostasis[1][2][5][6][7]. No currently approved drugs specifically and selectively target HERC2, but it could be considered a potential future therapeutic target due to its regulatory functions within important signaling and homeostatic pathways.

Other names

E3 ubiquitin-protein ligase HERC2jdf2p528D15F37S1HECT domain and RCC1-like domain-containing protein 2HECT-type E3 ubiquitin transferase HERC2MRT38SHEP1probable E3 ubiquitin-protein ligase HERC2

Drugs affecting HERC2 function would potentially alter protein ubiquitination, DNA repair fidelity, p53-mediated transcription, cell cycle progression, and iron metabolism[1][3][7].