UBE3A
UBE3A (E6-associated protein) is an E3 ubiquitin ligase whose loss causes Angelman syndrome and whose silencing in neurons is the classic human example of genomic imprinting.
Function
UBE3A tags substrate proteins with ubiquitin for proteasomal destruction. Its best-characterized substrate relationship runs in reverse: HPV E6 protein recruits UBE3A to p53, and the ligase ubiquitinates p53 for degradation — the mechanism by which HPV-positive tumors delete their p53 response without mutating the gene. UBE3A’s normal neuronal substrates include synaptic proteins, and its dosage in the brain shapes synaptic development.
Genomic imprinting
In most tissues both parental copies of UBE3A are active. In neurons the maternal copy alone is active: the paternal allele is silenced by the UBE3A-ATS long noncoding RNA. This parent-of-origin expression is genomic imprinting, and it makes the gene’s phenotype haploid in the brain. Loss of the maternal allele causes Angelman syndrome (severe developmental delay, seizures, ataxic gait); duplication of the maternal allele causes a subset of autism cases. The same dosage sensitivity explains why UBE3A is an autism candidate gene.
In cancer
In HPV-driven cancers, E6 hijacks UBE3A to destroy p53; in HPV-negative cancers UBE3A is more often overexpressed or amplified, acting as an oncogene through degradation of tumor-suppressive substrates.
Notes
- Human gene symbol: UBE3A; UniProt Q05086; 875 amino acids; HECT-domain E3 ligase; located in the 15q11-q13 imprinted region.