HERC2 Gene

Name	HECT and RLD domain containing E3 ubiquitin protein ligase 2
Description	This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HERC2, a large HECT‐type E3 ubiquitin ligase, has emerged as a multifunctional regulator in diverse biological processes. In the realm of pigmentation, common intronic variants in HERC2 have been shown to disrupt conserved regulatory elements that control the expression of the neighboring OCA2 gene, thereby contributing to human eye color variation and influencing skin pigmentation and even skin cancer risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, HERC2 has a critical role in tumor suppression through its interaction with p53, where it facilitates p53 oligomerization and thus enhances its transcriptional activity, influencing cell‐growth regulation and responses to DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " HERC2 also contributes to the regulation of iron homeostasis by promoting the turnover of the FBXL5 protein, which in turn affects cellular iron levels"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and it is involved in vascular homeostasis via a SIRT1‐dependent pathway that mediates the ubiquitination and proteasomal degradation of acetylated LKB1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond these roles, HERC2 maintains the fidelity of centriole duplication through its stabilization by NudCL2 and subsequent control of USP33 levels, thereby preventing centriole amplification, a process relevant to oncogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Differential expression of HERC2 is also linked to uveal melanoma prognosis, supporting its involvement in pigmentation pathways with oncogenic implications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, rare biallelic loss‐of‐function mutations and missense variants in HERC2 have been associated with severe neurodevelopmental disorders and may contribute to brain morphogenesis defects, as highlighted in studies reporting corpus callosum anomalies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HERC2 further participates in the DNA damage response by modulating ubiquitination cascades; for instance, ATR‐mediated phosphorylation leads to the dissociation of HERC2 from USP20, thereby stabilizing USP20 and enhancing ATR–Chk1 signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Gene–gene interaction analyses have implicated HERC2, along with other pigmentation genes such as MC1R and CDKN2A, in melanoma predisposition"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", while variants at the OCA2/HERC2 locus also affect the time to development of cutaneous squamous cell carcinomas."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the pleiotropic functions of HERC2—as a modulator of gene expression affecting pigmentation, as a regulator of tumor suppressor and DNA repair pathways, and as a key player in cell cycle control and neurodevelopment—which together have significant implications for human health and disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "9"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Richard A Sturm, David L Duffy, Zhen Zhen Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2007.11.005"}], "href": "https://doi.org/10.1016/j.ajhg.2007.11.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18252222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18252222"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sandra Beleza, Nicholas A Johnson, Sophie I Candille, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic architecture of skin and eye color in an African-European admixed population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003372"}], "href": "https://doi.org/10.1371/journal.pgen.1003372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23555287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23555287"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Monica Cubillos-Rojas, Fabiola Amair-Pinedo, Roser Peiró-Jordán, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.527978"}], "href": "https://doi.org/10.1074/jbc.M113.527978"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24722987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24722987"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Laura Bonanno, Carlota Costa, Margarita Majem, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12885-016-2339-5"}], "href": "https://doi.org/10.1186/s12885-016-2339-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27179511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27179511"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Toshiro Moroishi, Takayoshi Yamauchi, Masaaki Nishiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.541490"}], "href": "https://doi.org/10.1074/jbc.M113.541490"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24778179"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24778179"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Bo Bai, Andy W C Man, Kangmin Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9687"}], "href": "https://doi.org/10.18632/oncotarget.9687"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27259994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27259994"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Min Li, Xiaoyang Xu, Jun Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NudC-like protein 2 restrains centriole amplification by stabilizing HERC2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-1843-3"}], "href": "https://doi.org/10.1038/s41419-019-1843-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31427565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31427565"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Seema Kashyap, Mithalesh Kumar Singh, Jayanti Jha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic impact of HERC2 protein and pink-eyed dilution protein in uveal melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13577-020-00397-9"}], "href": "https://doi.org/10.1007/s13577-020-00397-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32686068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32686068"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Krista M Vincent, Alison Eaton, Vahid Reza Yassaee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Delineating the expanding phenotype of HERC2-related disorders: The impact of biallelic loss of function versus missense variation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.14039"}], "href": "https://doi.org/10.1111/cge.14039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34370298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34370298"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jolyane Meloche, Vanessa Brunet, Pierre-Alexandre Gagnon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequencing study of partial agenesis of the corpus callosum in men with developmental delay, epilepsy, and microcephaly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Genomic Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mgg3.992"}], "href": "https://doi.org/10.1002/mgg3.992"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31578829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31578829"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jian Yuan, Kuntian Luo, Min Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HERC2-USP20 axis regulates DNA damage checkpoint through Claspin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gku1034"}], "href": "https://doi.org/10.1093/nar/gku1034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25355518"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25355518"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Feifei Xiao, Jianzhong Ma, Guoshuai Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Natural and orthogonal model for estimating gene-gene interactions applied to cutaneous melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-013-1392-2"}], "href": "https://doi.org/10.1007/s00439-013-1392-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24241239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24241239"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Nilah M Ioannidis, Wei Wang, Nicholas A Furlotte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene expression imputation identifies candidate genes and susceptibility loci associated with cutaneous squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-06149-6"}], "href": "https://doi.org/10.1038/s41467-018-06149-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30323283"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30323283"}]}]}]}
Synonyms	JDF2, MRT38, D15F37S1, P528
Proteins	HERC2_HUMAN
NCBI Gene ID	8924
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HERC2 has 7,401 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 137 datasets.

Click the + buttons to view associations for HERC2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HERC2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HERC2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of HERC2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of HERC2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of HERC2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of HERC2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HERC2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of HERC2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HERC2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HERC2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of HERC2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HERC2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of HERC2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with HERC2 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with HERC2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HERC2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HERC2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HERC2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of HERC2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with HERC2 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with HERC2 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of HERC2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HERC2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HERC2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing HERC2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing HERC2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HERC2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with HERC2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HERC2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HERC2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HERC2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with HERC2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by HERC2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving HERC2 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving HERC2 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with HERC2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with HERC2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HERC2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with HERC2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with HERC2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HERC2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.