HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases

Homologous to the E6AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing proteins (HERCs) belong to the superfamily of ubiquitin ligases. HERC proteins are divided into two subfamilies, Large and Small HERCs. Despite their similarities in terms of both structure and domains, these subfamilies are evolutionarily very distant and result from a convergence phenomenon rather than from a common origin. Large HERC genes, HERC1 and HERC2, are present in most metazoan taxa. They encode very large proteins (approximately 5,000 amino acid residues in a single polypeptide chain) that contain more than one RCC1-like domain as a structural characteristic. Accumulating evidences show that these unusually large proteins play key roles in a wide range of cellular functions which include neurodevelopment, DNA damage repair, and cell proliferation. To better understand the origin, evolution, and function of the Large HERC family, this minireview provides with an integrated overview of their structure and function and details their physiological implications. This study also highlights and discusses how dysregulation of these proteins is associated with severe human diseases such as neurological disorders and cancer.

• Publication year

  2019

• Venue

  Frontiers in Physiology

• Publication date

  2019-08-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fphys.2019.01014PMID 31447701PMCID 6692442
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Interactive Tree Of Life (iTOL) v4: recent updates and new developments

  2019cited by this paper
• HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System

  2018cited by this paper
• Genetic variants associated with skin photosensitivity in a southern European population from Spain

  2018cited by this paper
• SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

  2018cited by this paper
• Genome profile in a extremely rare case of pulmonary sclerosing pneumocytoma presenting with diffusely-scattered nodules in the right lung

  2018cited by this paper
• The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

  2018cited by this paper
• Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes

  2018cited by this paper
• SWISS-MODEL: homology modelling of protein structures and complexes

  2018cited by this paper
• HERC2 Facilitates BLM and WRN Helicase Complex Interaction with RPA to Suppress G-Quadruplex DNA.

  2018cited by this paper
• Heterogeneous expression and biological function of SOX18 in osteosaroma

  2018cited by this paper
• HERC1 mutations in idiopathic intellectual disability.

  2017cited by this paper
• Comparative analysis of microRNA and mRNA expression profiles in cells and exosomes under toluene exposure.

  2017cited by this paper
• Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells.

  2017cited by this paper
• NEURL4 regulates the transcriptional activity of tumor suppressor protein p53 by modulating its oligomerization

  2017cited by this paper
• UFBoot2: Improving the Ultrafast Bootstrap Approximation

  2017cited by this paper
• Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala

  2017cited by this paper
• WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

  2017cited by this paper
• RNF8/UBC13 ubiquitin signaling suppresses synapse formation in the mammalian brain

  2017cited by this paper
• The cargo protein MAP17 (PDZK1IP1) regulates the immune microenvironment

  2017cited by this paper
• ModelFinder: Fast Model Selection for Accurate Phylogenetic Estimates

  2017cited by this paper
• Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

  2016cited by this paper
• Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

  2016cited by this paper
• UniProt: the universal protein knowledgebase

  2016cited by this paper
• ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast

  2016cited by this paper
• A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

  2016cited by this paper
• Functional and pathological relevance of HERC family proteins: a decade later

  2016cited by this paper
• Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype

  2016cited by this paper
• The role of HERC2 and RNF8 ubiquitin E3 ligases in the promotion of translesion DNA synthesis in the chicken DT40 cell line.

  2016cited by this paper
• The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination

  2016cited by this paper
• Structural insights into the catalysis and regulation of E3 ubiquitin ligases

  2016cited by this paper
• HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

  2016cited by this paper
• A twin sibling with Prader-Willi syndrome caused by type 2 microdeletion following assisted reproductive technology: A case report

  2016cited by this paper
• Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder

  2015cited by this paper
• Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability

  2015cited by this paper
• A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

  2015cited by this paper
• The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction

  2015cited by this paper
• Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.

  2015cited by this paper
• Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis

  2015cited by this paper
• Resistance to UV‐induced apoptosis by β‐HPV5 E6 involves targeting of activated BAK for proteolysis by recruitment of the HERC1 ubiquitin ligase

  2015cited by this paper
• The Parkinson’s Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway

  2015cited by this paper
• Eye color: A potential indicator of alcohol dependence risk in European Americans

  2015cited by this paper
• TUSC4 functions as a tumor suppressor by regulating BRCA1 stability.

  2015cited by this paper
• IQ-TREE: A Fast and Effective Stochastic Algorithm for Estimating Maximum-Likelihood Phylogenies

  2014cited by this paper
• HERC2 Targets the Iron Regulator FBXL5 for Degradation and Modulates Iron Metabolism

  2014cited by this paper
• Proteomic Analysis and Identification of Cellular Interactors of the Giant Ubiquitin Ligase HERC2

  2014cited by this paper
• Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects

  2014cited by this paper
• Structural and functional insights to ubiquitin-like protein conjugation.

  2014cited by this paper
• The Histone H 2 A Deubiquitinase USP 16 Interacts with HERC 2 and Fine-tunes Cellular Response to DNA Damage *

  2014cited by this paper
• Sunlight exposure, pigmentation, and incident age-related macular degeneration.

  2014cited by this paper
• The E3 Ubiquitin Protein Ligase HERC2 Modulates the Activity of Tumor Protein p53 by Regulating Its Oligomerization*

  2014cited by this paper
• Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair

  2014cited by this paper
• Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y

  2014cited by this paper
• HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability

  2014cited by this paper
• Mutational spectrum of adult T-ALL

  2014cited by this paper
• Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services.

  2014cited by this paper
• The Histone H2A Deubiquitinase USP16 Interacts with HERC2 and Fine-tunes Cellular Response to DNA Damage*

  2014cited by this paper
• HERC2-USP20 axis regulates DNA damage checkpoint through Claspin

  2014cited by this paper
• Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion.

  2013cited by this paper
• IQGAP1 is a key node within the small GTPase network

  2013cited by this paper
• Genetics of eye colours in different rural populations on the Silk Road

  2013cited by this paper
• New and continuing developments at PROSITE

  2012cited by this paper
• Genome and Transcriptome Sequencing in Prospective Metastatic Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities

  2012cited by this paper
• DNA damage–inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger

  2012cited by this paper
• Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

  2012cited by this paper
• RNF8 and RNF168 but not HERC2 are required for DNA damage-induced ubiquitylation in chicken DT40 cells.

  2012cited by this paper
• A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder

  2012cited by this paper
• HECT and RING finger families of E3 ubiquitin ligases at a glance

  2012cited by this paper
• The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo

  2012cited by this paper
• HERC2 interacts with Claspin and regulates DNA origin firing and replication fork progression

  2012cited by this paper
• Mutation of HERC2 causes developmental delay with Angelman-like features

  2012cited by this paper
• Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.

  2011cited by this paper
• Frameshift mutations of ubiquitination-related genes HERC2, HERC3, TRIP12, UBE2Q1 and UBE4B in gastric and colorectal carcinomas with microsatellite instability.

  2011cited by this paper
• The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo.

  2011cited by this paper
• HERC2 Interacts with Claspin and regulates DNA origin firing and replication fork progression.

  2011cited by this paper
• Physical and Functional Interaction of the HECT Ubiquitin-protein Ligases E6AP and HERC2*

  2011cited by this paper
• Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells

  2011cited by this paper
• HERC2 is an E3 ligase that targets BRCA1 for degradation.

  2010cited by this paper
• Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.

  2010cited by this paper
• Animal HECT ubiquitin ligases: evolution and functional implications

  2010influential reference
• Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2

  2010cited by this paper
• Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase

  2010cited by this paper
• HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes

  2010cited by this paper
• HERC 2 Is an E 3 Ligase That Targets BRCA 1 for Degradation

  2010cited by this paper
• Identification of LPS‐inducible genes downregulated by ubiquinone in human THP‐1 monocytes

  2010cited by this paper
• Atypical mRNA fusions in PML‐RARA positive, RARA‐PML negative acute promyelocytic leukemia

  2010cited by this paper
• Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein

  2010cited by this paper
• Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes

  2010cited by this paper
• Assembly and function of DNA double-strand break repair foci in mammalian cells.

  2010cited by this paper
• Confirmation of Multiple Crohn's Disease Susceptibility Loci in a Large Dutch–Belgian Cohort

  2009cited by this paper
• Genome-wide association study of tanning phenotype in a population of European ancestry.

  2009cited by this paper
• Population Differentiation as an Indicator of Recent Positive Selection in Humans: An Empirical Evaluation

  2009cited by this paper
• Interactions Between HERC2, OCA2 and MC1R May Influence Human Pigmentation Phenotype

  2009cited by this paper
• HERC1 polymorphisms: population‐specific variations in haplotype composition

  2009cited by this paper
• Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

  2009cited by this paper
• A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.

  2008cited by this paper
• Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression

  2008cited by this paper
• The RCC1 superfamily: from genes, to function, to disease.

  2008influential reference
• Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.

  2008cited by this paper
• Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis

  2008cited by this paper
• Pyruvate kinase type M2: a key regulator within the tumour metabolome and a tool for metabolic profiling of tumours.

  2007cited by this paper

• Hepatocyte-expressed HERC2 enhances type I interferon-mediated anti-HBV immune response by promoting K33 ubiquitination of TBK1.

  2025cites this paper
• Unveiling EIF5A2: A Multifaceted Player in Cellular Regulation, Tumorigenesis and Drug Resistance.

  2025cites this paper
• The mechanism of E3 ubiquitin ligase HERC1 regulating ferroptosis in lung adenocarcinoma cells.

  2025cites this paper
• NCOA4-dependent ferritinophagy drives perfluorooctanoic acid-triggered renal ferroptosis in chicken embryos.

  2025cites this paper
• DNA repair and inflammatory response genes play a central role in protecting patients with long-standing type 1 diabetes from vascular complications.

  2025cites this paper
• Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder

  2024cites this paper
• Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder

  2024cites this paper
• Hesperidin alleviated dendritic spines through inhibiting ferritinophagy via HERC2-NCOA4 ubiquitination in CUMS mice.

  2024cites this paper
• Hepatocyte‐Targeted Lipid Nanoparticle Delivery of HERC2 Plasmid Controls Drug‐Induced Hepatotoxicity by Limiting β‐Catenin‐Regulated CYP2E1 Expression

  2024cites this paper
• The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN

  2023cites this paper
• Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5

  2023cites this paper
• Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases

  2023cites this paper
• HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway

  2023cites this paper
• Identification of candidate SNPs and genes associated with resistance to nervous necrosis virus in leopard coral grouper (Plectropomus leopardus) using GWAS.

  2023cites this paper
• Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

  2023cites this paper
• Validation of a murine proteome-wide phage display library for identification of autoantibody specificities

  2023cites this paper
• A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF–7 Cells via the HERC3/p53 Signaling Pathway

  2022cites this paper
• The Herc1 gene in neurobiology.

  2022cites this paper
• The Downregulation of Both Giant HERCs, HERC1 and HERC2, Is an Unambiguous Feature of Chronic Myeloid Leukemia, and HERC1 Levels Are Associated with Leukemic Cell Differentiation

  2022cites this paper
• Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing

  2022cites this paper
• Modulation of autoimmune diabetes by N-ethyl-N-nitrosourea- induced mutations in non-obese diabetic mice

  2022cites this paper
• HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress

  2022cites this paper
• Ubiquitin pathways regulate the pathogenesis of chronic liver disease.

  2021cites this paper
• Identification of a quality-control factor that monitors failures during proteasome assembly

  2021cites this paper
• The HERC proteins and the nervous system.

  2021cites this paper
• The fellowship of the RING: BRCA1, its partner BARD1 and their liaison in DNA repair and cancer.

  2021cites this paper
• The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

  2020cites this paper
• Structure and Function of HECT E3 Ubiquitin Ligases and their Role in Oxidative Stress

  2020cites this paper
• HERC Ubiquitin Ligases in Cancer

  2020cites this paper
• Rub1/NEDD8, a ubiquitin-like modifier, is also a ubiquitin modifier

  2020cites this paper
• A Genome-Wide Screen in Mice To Identify Cell-Extrinsic Regulators of Pulmonary Metastatic Colonisation

  2020cites this paper
• Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

  2020cites this paper
• HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory

  2020cites this paper
• Structural Insight into Binding of the ZZ Domain of HERC2 to Histone H3 and SUMO1.

  2020cites this paper
• Gene discovery and cellular modelling of rare autosomal recessive neurodevelopmental conditions

  2019cites this paper
• Regulation of the MDM2‐p53 pathway by the ubiquitin ligase HERC2

  2019cites this paper