HERC2 is a giant E3 ubiquitin protein ligase, implicated in DNA repair regulation, pigmentation and neurological disorders. It is encoded by a gene of the same name belonging to the HERC family, which typically encodes large protein products with C-terminal HECT domains and one or more RCC1-like (RLD) domains.^[1][2]

HERC2, previously referred to as the rjs gene locus, was first identified in 1990 as the gene responsible for two phenotypes in mice: the runty, jerky, sterile (rjs) phenotype and the juvenile development and fertility-2 (Jdf2) phenotype. Mutant alleles are known to cause hypo-pigmentation and pink eye phenotypes, as well reduced growth, jerky gait, male sterility, female semi-sterility, and maternal behaviour defects in mice.^[3][4][5]

The full HERC2 gene is located at 15q13, encoded by 93 exons and its transcription is under the control of a CpG rich promoter. This region on chromosome 15 is susceptible to breaks during chromosomal rearrangement and there are at least 12 partial duplicates of HERC2 between 15q11–15q13.^[6]

At least 15 HERC2 SNPs have been identified and they are strongly associated with human iris colour variability, functioning to repress expression of OCA2's product.^[7]

HERC2 encodes a 4834-amino acid protein with a theoretical size of 528 kDa. While a full structure has not yet been elucidated, potentially due to its large size, partial structures of its domains have been captured.^[8]

It has an N-terminal bilobed HECT domain, conferring E3 ligase functionality, as well as 3 RLD domains with seven-bladed β-propeller folds. In addition to these HERC family hallmarks, it has several other motifs; a cytochrome-b5-like domain, several potential phosphorylation sites, and a ZZ-type zinc finger motif.^[1] This is likely involved in protein binding, and has recently been identified as a SUMOylation target following DNA damage.^[9]

Expression of HERC2 is ubiquitous, though particularly high in the brain and testes. Cellular localisation is predominantly to the nucleus and cytoplasm.^[1]

The 15q11-q13 locus of HERC2 is also associated with Angelman syndrome (AS), specifically when a region of this locus is deleted. Similar to the rjs phenotype attributed to HERC2 in mice, AS is associated with seizures, developmental delay, intellectual disability and jerky movements. While a variety of disturbances to this locus can cause AS, all known mechanisms affect the functioning and expression of the E6AP E3 ligase, which also sits at this locus. HER2 is an allosteric activator of E6AP, and lies at the most commonly deleted region in AS.^[27] Its deletion could result in the inactivation of E6AP and consequently the development of AS.^[28]

In Old Order Amish families, a homozygous proline to leucine missense mutation within the first RLD domain has been implicated in a neurodevelopmental disorder with autism and features resembling AS.^[29] In addition, a homozygous deletion of both OCA2 and HERC2 genes was recently reported as presenting with severe developmental abnormalities.^[30] These phenotypes are suggestive of a role for HERC2 in normal neurodevelopment.

Certain alleles of HERC2 has recently been implicated in increasing the risk of iris cancer. Due its role in pigment determination, three HERC2 SNPs have been highlighted as associated with uveal melanoma.^[31] HERC2 frameshift mutations have also been described in colorectal cancers.^[32]

In accordance to its role in facilitating p53 oligomerization, HERC2 may be causally related to Li-Fraumeni syndrome and Li-Fraumeni-like syndromes, which occur in the absence of sufficient p53 oligomerization.^[26]

HERC2 is known to interact with the following:

• RNF8^[21]
• FBXL5^[25]
• OCA2^[15]
• UBC13^[21]
• USP20^[18][19]
• XPA^[22][23]
• Claspin^[18][19][20]
• E6AP^[27]
• NEURL4^[24]
• RNF168^[21]
• BRCA1^[33]
• p53^[26]
• LRRK2^[34]

• Angelman Syndrome
• Eye color
• DNA repair pathways