E3 ubiquitin-protein ligase HERC2

HERC2 is an E3 ubiquitin-protein ligase that regulates DNA damage response and repair by mediating ubiquitin-chain formation at sites of chromosomal damage. It facilitates assembly of repair protein complexes through interactions with UBE2N and RNF8, and also controls proteasomal degradation of DNA repair factors like XPA and iron-metabolism proteins (UniProt: O95714). Beyond DNA repair, HERC2 influences insulin-like growth factor receptor signaling and iron homeostasis by modulating FBXL5 turnover.

HERC2 is implicated in neurodevelopmental disease; mutations cause intellectual developmental disorder with autistic features (MRT38, MIM 615516), characterized by global developmental delay and behavioral symptoms including autism spectrum features and self-injurious behavior (UniProt: O95714).

In Alzheimer's disease, HERC2 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC −0.51; Chaparral AD proteomics). The data derive from TMT-labeled quantitative proteomics across four subcellular fractions. The functional consequences of reduced HERC2 in AD pathology remain to be determined, though diminished DNA repair capacity and altered growth factor signaling may be relevant to neurodegeneration.