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HERC2

HERC2, or HECT and RLD domain containing E3 ubiquitin protein ligase 2, is a human gene located on the long arm of chromosome 15 at position 15q13.1 that encodes a large multifunctional E3 ubiquitin ligase protein of 4,834 amino acids and approximately 527 kDa in size.^[1]^[2] This protein, which shuttles between the nucleus and cytoplasm, plays critical roles in ubiquitin-dependent processes such as protein degradation, DNA damage repair, and cell cycle regulation by targeting substrates like BRCA1 and XPA for ubiquitination.^[3]^[2] HERC2 belongs to the HERC family of proteins, characterized by HECT and RCC1-like domains (RLD), and is ubiquitously expressed with particularly high levels in fetal tissues, skeletal muscle, heart, brain, ovary, and testis.^[1]^[2] Beyond its core enzymatic function, HERC2 facilitates the assembly of DNA repair complexes at damaged sites, promotes the retention of repair proteins on chromosomes, and interacts with key regulators such as p53 to enhance its oligomerization and transcriptional activity, thereby contributing to tumor suppression.^[3]^[4] It also modulates mitochondrial dynamics, spindle formation during mitosis, and antigen processing pathways, underscoring its involvement in cellular homeostasis and development.^[5]^[1] Notably, HERC2 influences pigmentation traits through regulatory variants, such as the single nucleotide polymorphism rs12913832, which affects iris color and is a major determinant of blue versus brown eyes in populations of European descent.^[2] Mutations in HERC2 are associated with severe neurodevelopmental disorders, including autosomal recessive intellectual developmental disorder 38 (MIM 615516), characterized by profound developmental delay, hypotonia, seizures, and early lethality, as seen in cases of complete loss-of-function frameshift variants leading to mitochondrial dysfunction and disrupted protein interactions.^[2]^[5] Additionally, variants contribute to variations in skin, hair, and eye pigmentation (MIM 227220), highlighting HERC2's pleiotropic effects.^[2] Research continues to elucidate its roles in cancer progression, such as promoting inflammation-driven stemness in hepatocellular carcinoma via STAT3 activation, emphasizing its potential as a therapeutic target.^[4]

Discovery and History

Initial Identification

The HERC2 gene was first identified in 1998 through positional cloning of the runty, jerky, sterile (rjs) locus on mouse chromosome 7, where homozygous mutations cause phenotypes including postnatal growth retardation, neurological abnormalities such as ataxia and tremors, male sterility due to sperm defects, and mild hypopigmentation.^[6] The encoded protein was noted for its large size (4,836 amino acids) and possession of a C-terminal HECT domain characteristic of E3 ubiquitin ligases, along with N-terminal RCC1-like domains (RLDs) involved in guanine nucleotide exchange.^[6] Early cloning and sequencing efforts in the late 1990s, building on the recent discovery of the related HERC1 gene in 1996, established HERC2 as the second member of the HERC family of E3 ubiquitin ligases, distinguished by their combined HECT and RLD architectures that enable both ubiquitination and regulation of small GTPases.^[7]^[6] The human HERC2 homolog was identified shortly thereafter in 1999 via comparative genomics between mouse and human sequences, revealing a highly conserved giant protein of 4,834 amino acids and mapping the gene to chromosome 15q13.1 within the Prader-Willi/Angelman syndrome critical region.^[8] Subsequent functional studies have explored HERC2's roles in pigmentation regulation and DNA repair mechanisms.

Key Research Milestones

The identification of HERC2's role in regulating OCA2 expression emerged as a pivotal discovery in human pigmentation genetics. In 2008, researchers identified a single nucleotide polymorphism (SNP), rs12913832, located in an enhancer region within intron 86 of the HERC2 gene, which strongly predicts blue versus brown eye color by modulating OCA2 transcription levels in melanocytes of the iris.^[9] This finding highlighted HERC2's influence on phenotypic variation and established it as a key regulator of oculocutaneous albinism type 2 (OCA2)-related traits. Subsequent research in the late 2000s and early 2010s advanced understanding of HERC2's involvement in DNA damage response pathways. Between 2008 and 2010, studies demonstrated that HERC2 acts as an E3 ubiquitin ligase coordinating the assembly of repair factors at DNA double-strand breaks, particularly through interactions that facilitate BRCA1 recruitment and Chk1 kinase activation during the G2/M checkpoint. These insights underscored HERC2's tumor-suppressive functions and its role in maintaining genomic stability. Post-2010 milestones expanded HERC2's functional repertoire beyond pigmentation and repair. In 2012, proteomic interaction studies revealed HERC2's association with NEURL4 at the centrosome, where the complex modulates centriole integrity and mitotic progression by regulating CP110 ubiquitination, linking HERC2 to ciliogenesis and cell cycle control. Building on this, research from 2014 onward elucidated HERC2's regulation of iron homeostasis; specifically, HERC2 promotes the ubiquitination and degradation of FBXL5, an iron sensor, thereby fine-tuning cellular iron levels and preventing oxidative stress.^[10] In the 2020s, genetic studies have confirmed HERC2's neurological contributions, with loss-of-function variants underlying severe neurodevelopmental disorders resembling Angelman syndrome, characterized by intellectual disability, seizures, and structural brain abnormalities due to disrupted ubiquitination in neuronal development.^[5] These efforts build on foundational 1990s mouse mutant models, such as the rjs/jdf2 strains, which exhibited sterility, runting, and neurological deficits attributable to Herc2 disruptions.^[11] More recent work (2023–2025) has implicated HERC2 in cancer progression, including promotion of inflammation-driven stemness in hepatocellular carcinoma and oncogenic roles in familial glioma.^[12]^[13]

Genomics

Gene Locus and Structure

The HERC2 gene is located on the long arm of human chromosome 15 at the q13.1 cytogenetic band.^[4] In the GRCh38.p14 reference assembly, it occupies genomic coordinates 28,111,040 to 28,322,179 on the reverse (complementary) strand, spanning approximately 211 kb.^[4] The gene comprises 98 exons, which encode multiple protein isoforms through alternative splicing.^[4] The promoter region of HERC2 is characterized by a CpG island at its 5' end, which facilitates transcription initiation.^[14] This CpG-rich promoter harbors regulatory elements that contribute to tissue-specific expression patterns of the gene.^[15] Intron-exon boundaries generally adhere to consensus splice site sequences, enabling precise processing of pre-mRNA.^[14] Alternative splicing of HERC2 generates at least 14 distinct transcripts, reflecting the complexity of its genomic organization.^[16] The longest canonical transcript, NM_004667.6, produces a protein of 4,834 amino acids.^[4] The HERC2 locus exhibits high conservation across mammalian species, with orthologs identified in over 200 vertebrates, including the mouse Herc2 gene on chromosome 7. However, certain mouse strains harbor deletions that encompass the Herc2 gene, as seen in alleles associated with the Oca2 locus.^[17]

Expression Patterns and Regulation

The HERC2 gene exhibits ubiquitous basal expression across human tissues, with particularly elevated levels observed in the nervous system, including the sural nerve and the right hemisphere of the cerebellum, as well as in the testes and retina.^[1]^[18] According to data from the GTEx and Bgee databases, HERC2 is detected in 94 distinct cell types or tissues, underscoring its broad role in cellular processes, though transcript abundance is notably higher in neural and reproductive tissues.^[1] During development, HERC2 expression peaks in embryonic stages, with protein levels reaching maximum at around embryonic day 16 in mice, before declining postnatally and in adulthood.^[19] This pattern aligns with its essential function in early embryogenesis, as homozygous mutations lead to lethality before embryonic day 7.5, and high expression persists in brain regions associated with neurogenesis, such as the hippocampus, amygdala, and cerebellum.^[19] In the testes, elevated expression suggests involvement in gametogenesis.^[1] HERC2 modulates p53-dependent expression of MDM2 and participates in a feedback loop within the p53-MDM2 pathway through interactions in a complex with p53 and NEURL4, influencing pathway dynamics under DNA damage conditions.^[20] Although direct evidence for p53 directly controlling HERC2 transcription is limited, the interaction complex involving HERC2, p53, and NEURL4 responds to genotoxic stress, potentially linking HERC2 levels to cellular responses.^[20] In melanocytes, HERC2 expression contributes to pigmentation regulation, as intronic variants in the gene influence downstream effects on melanin production.^[1]

Protein Characteristics

Domain Architecture

The HERC2 protein is a large multidomain E3 ubiquitin ligase composed of 4,834 amino acids, with a calculated molecular weight of approximately 527 kDa.^[3] Its domain architecture is characterized by a modular arrangement that supports its roles in ubiquitination and protein interactions, spanning from the N-terminus to the C-terminus.^[21] At the C-terminus, HERC2 features the signature HECT (Homologous to the E6-AP Carboxyl Terminus) domain, spanning residues 4,457–4,794, which confers E3 ubiquitin ligase activity.^[22] This domain contains a conserved catalytic cysteine residue at position 4,762, which forms a thioester intermediate with ubiquitin during the transfer process to substrates.^[23] In the N-terminal region, HERC2 possesses three RCC1-like domains (RLDs), located at approximately residues 415–778 (RLD1), 2,958–3,327 (RLD2), and 3,951–4,319 (RLD3), which adopt a seven-bladed β-propeller structure similar to RCC1 and function as guanine nucleotide exchange factors, particularly influencing the activity of small GTPases like Ran.^[22] These RLDs are crucial for intramolecular regulation of the HECT domain's ubiquitination activity.^[21] HERC2 also includes additional motifs for protein binding, such as ZZ-type zinc finger domains, including one at residues 2,702–2,755, which coordinate zinc ions and mediate binding to targets like histone H3 and SUMO1.^[21]^[22]

Biophysical Properties

The HERC2 protein primarily localizes to the cytoplasm across various tissues, while also exhibiting nuclear and nucleolar distribution, particularly at sites of DNA damage or replication forks.^[24]^[25] This dual localization enables HERC2 to participate in diverse cellular processes, and it shuttles between the nucleus and cytoplasm to facilitate its functions as an E3 ubiquitin ligase.^[26] The shuttling is mediated by nuclear localization signals (NLS) and nuclear export signals (NES) embedded in its sequence, allowing dynamic redistribution in response to cellular cues.^[26] HERC2 tends to oligomerize, forming dimers or higher-order complexes that are critical for its ubiquitin ligase activity and substrate recognition. Structural analyses reveal that segments of HERC2, such as residues 2540–2700, dimerize in complexes with partners like NCOA4, promoting efficient ubiquitination.^[27]^[28] This oligomerization is a shared feature among large HECT-domain E3 ligases, enhancing their regulatory roles. The stability of HERC2 is modulated by auto-ubiquitination, whereby the protein ubiquitinates itself, leading to proteasomal degradation and turnover.^[28] This self-regulatory mechanism, typical of HECT E3 ligases, maintains appropriate protein levels in unstressed cells and can be disrupted in mutants, resulting in altered half-lives.^[29] HERC2 has a predicted isoelectric point (pI) of approximately 5.88, reflecting its net charge profile under physiological conditions.^[30] The protein demonstrates good solubility in aqueous buffers, as it is predominantly recovered in soluble cellular fractions rather than insoluble aggregates.^[5] Its ubiquitous expression pattern further supports this broad subcellular distribution and functional versatility.^[31]

Biological Functions

Regulation of Pigmentation

HERC2 plays a pivotal role in pigmentation regulation primarily through a melanocyte-specific enhancer element located in intron 86, harboring the single nucleotide polymorphism (SNP) rs12913832. This SNP lies approximately 21 kb upstream of the OCA2 gene, which encodes a melanosomal transmembrane protein crucial for maintaining optimal pH in melanosomes to facilitate melanin synthesis. The ancestral G allele (brown eye-associated) at rs12913832 promotes chromatin looping between the enhancer and the OCA2 promoter, thereby enhancing OCA2 transcription and leading to increased melanin production and darker pigmentation. In contrast, the derived A allele (blue eye-associated) disrupts this looping, resulting in reduced OCA2 expression and lighter pigmentation traits, such as blue eyes and fair skin.^[32] The enhancer activity is modulated by transcription factors, including the microphthalmia-associated transcription factor (MITF), which preferentially binds to the G allele, further amplifying OCA2 expression in melanocytes. MITF, a master regulator of melanocyte differentiation and melanin biosynthesis, interacts with the enhancer alongside other factors like HLTF and LEF1 to facilitate the chromatin conformation necessary for promoter activation. This binding preference underscores HERC2's indirect influence on MITF-driven pathways, where allelic variation at rs12913832 fine-tunes melanogenic gene expression without altering HERC2 protein function itself.^[32] HERC2 variants also exhibit epistatic interactions with TYRP1, a gene encoding tyrosinase-related protein 1 involved in eumelanin stabilization and the balance between eumelanin (dark pigment) and pheomelanin (red-yellow pigment). Specifically, combinations of rs12913832 in HERC2 and polymorphisms in TYRP1, such as rs13289810, show synergistic effects on eye color determination, with certain haplotypes enhancing the likelihood of green or intermediate shades. These genetic interactions contribute to the polygenic nature of pigmentation traits beyond OCA2 alone.^[33] At the population level, the A allele of rs12913832 represents a hypomorphic variant that emerged approximately 6,000–10,000 years ago in European populations, rapidly increasing in frequency due to positive selection and now accounting for up to 74% of variation in blue versus brown eye color in Europeans. This allele's prevalence is notably lower in non-European groups, highlighting HERC2's role in recent human evolutionary adaptations to varying UV exposure levels, where reduced pigmentation may confer photoprotective advantages in low-sunlight environments.^[34]00842-7)

DNA Repair Mechanisms

HERC2, an E3 ubiquitin ligase, plays a pivotal role in coordinating DNA damage response pathways by modulating the stability and localization of key repair proteins through ubiquitination.^[35] In response to genotoxic stress, HERC2 facilitates the assembly of ubiquitin-dependent signaling cascades that ensure efficient repair of DNA lesions, including double-strand breaks (DSBs) and UV-induced damage.^[36] HERC2 contributes to the activation of the checkpoint kinase Chk1 following DNA damage by regulating Claspin stability via its interaction with the deubiquitinase USP20. Under normal conditions, HERC2 ubiquitinates and promotes the degradation of USP20, which in turn limits USP20-mediated deubiquitination of Claspin, keeping Claspin levels low.^[37] Upon DNA damage, ATR phosphorylates USP20 at SQ/TQ motifs, disrupting the HERC2-USP20 complex and stabilizing USP20, which then deubiquitinates Claspin to enhance its accumulation.^[37] This stabilization of Claspin promotes its interaction with ATR and Chk1, facilitating Chk1 phosphorylation and activation of the replication checkpoint, as evidenced by reduced Chk1 phosphorylation in USP20-depleted cells exposed to hydroxyurea or UV.^[37] Experimental co-immunoprecipitation and deubiquitination assays confirm that HERC2's E3 activity is essential for this dynamic regulation, with HERC2 depletion leading to USP20 stabilization and prolonged checkpoint signaling.^[37] In homologous recombination (HR) repair of DSBs, HERC2 recruits RNF8 to damage sites to initiate histone ubiquitination. DNA damage induces PIAS4-mediated SUMOylation of HERC2 at lysine residues, which, in conjunction with ATM/ATR-dependent phosphorylation at Thr4827, exposes the ZZ zinc finger domain of HERC2 to bind SUMO1 and stabilize the RNF8-Ubc13 complex.^[36] This interaction promotes RNF8's E3 ligase activity, leading to K63-linked ubiquitination of histones H2A and H2AX at DSBs, which recruits downstream factors like RNF168 and BRCA1 for error-free repair.^[36] Isothermal titration calorimetry demonstrates the ZZ domain's specific SUMO1 binding (Kd ≈ 3 µM), and PIAS4 knockdown abolishes HERC2-RNF8 association and RNF168 foci formation post-irradiation, underscoring HERC2's role in ubiquitin chain elongation.^[36] HERC2 depletion impairs this process, resulting in defective retention of repair proteins and increased cellular sensitivity to ionizing radiation.^[35] HERC2 also modulates nucleotide excision repair (NER) by ubiquitinating the xeroderma pigmentosum A (XPA) protein, which is crucial for recognizing and excising UV-induced DNA adducts. In undamaged cells, HERC2 binds and ubiquitinates XPA, targeting it for proteasomal degradation to maintain basal levels.^[38] Upon UV exposure, ATR phosphorylates XPA at Ser196, which disrupts the HERC2-XPA interaction, inhibits ubiquitination, and stabilizes XPA for recruitment to damage sites.^[38] Phosphomimetic XPA mutants (S196D) exhibit reduced HERC2 binding and enhanced chromatin retention, leading to improved NER efficiency and faster removal of cyclobutane pyrimidine dimers, as shown in XPA-deficient cells complemented with mutants.^[38] This coordinated regulation ensures timely XPA availability without excessive accumulation that could disrupt repair fidelity.^[38] HERC2 integrates with the BRCA1 complex to support error-free DSB repair, primarily by regulating BRCA1 stability through targeted ubiquitination. HERC2 ubiquitinates BRCA1 at its N-terminal degron when BRCA1 is uncoupled from BARD1, promoting its degradation during S phase to fine-tune repair timing.^[39] This activity requires HERC2's catalytic cysteine (Cys4762) and is inhibited by BARD1 binding, allowing BRCA1 accumulation for HR when needed.^[39] HERC2 depletion restores BRCA1 levels and enhances G2-M checkpoint function in BARD1-low cells, linking it to HR proficiency.^[39] Loss-of-function mutations in HERC2, as observed in patient fibroblasts, result in BRCA1 accumulation alongside reduced HR activity, indicating that precise BRCA1 turnover is essential for efficient repair.^[40] Similarly, these cells show elevated XPA levels but impaired NER, highlighting HERC2's role in balancing protein homeostasis for genomic integrity.^[40] Mouse knockouts of HERC2 are embryonic lethal, with conditional models revealing repair defects and increased genomic instability.^[41] HERC2's regulation of BRCA1 overlaps briefly with p53 stabilization in stressed cells to coordinate repair and apoptosis.^[35]

Centrosome and Mitotic Functions

HERC2 plays a critical role in maintaining centrosome integrity during interphase and mitosis by acting as an E3 ubiquitin ligase that targets NEURL4 for proteasomal degradation via K48-linked ubiquitination. This process prevents the accumulation of NEURL4 at centrosomes, thereby regulating pericentriolar material (PCM) assembly and avoiding aberrant centrosome amplification. In U2OS cells, HERC2 and NEURL4 colocalize at centrosomes during interphase but dissociate upon mitotic entry, ensuring proper centrosome function without interference during spindle formation.^[42] Through its regulation of NEURL4, HERC2 ensures organized PCM assembly, which is essential for the recruitment of structural proteins like pericentrin and CEP135, thereby promoting bipolar spindle formation in mitosis. Depletion of HERC2 in U2OS or HeLa cell lines disrupts this architecture, leading to elongated, filamentous PCM structures and increased centrosome numbers, with approximately 3-fold more cells exhibiting supernumerary centrioles (>4 per cell). Although HERC2 does not directly interact with gamma-tubulin ring complexes (γ-TuRCs), its maintenance of PCM integrity indirectly supports γ-TuRC docking and microtubule nucleation at centrosomes.^[42] HERC2 depletion results in mitotic defects, including a significant rise in pseudobipolar spindles—observed in up to 20% of mitotic U2OS cells—due to fragmented or amplified centrosomes that fail to properly organize microtubules. These abnormalities promote chromosome missegregation, lagging chromosomes, and aneuploidy, as evidenced by increased chromosomal instability in depleted cell lines. HERC2's mitotic roles also tie briefly to DNA repair pathways activated at the G2/M checkpoint, where its ubiquitin ligase activity helps coordinate genome stability during cell division.^[42]

Iron Homeostasis

HERC2 plays a critical role in cellular iron sensing by acting as an E3 ubiquitin ligase that targets the iron-responsive repressor FBXL5 for proteasomal degradation, particularly under low-iron conditions. This ubiquitination process destabilizes FBXL5, preventing it from promoting the degradation of iron regulatory protein 2 (IRP2). As a result, IRP2 accumulates and binds to iron-responsive elements (IREs) in the mRNA of transferrin receptor 1 (TFRC), stabilizing TFRC transcripts and enhancing its expression on the cell surface to facilitate iron uptake via receptor-mediated endocytosis. This mechanism ensures efficient coordination with TFRC trafficking, allowing cells to increase iron import in response to iron deficiency.^[43]^[44] In high-iron conditions, HERC2 shifts its activity to ubiquitinate nuclear receptor coactivator 4 (NCOA4), marking it for degradation and thereby inhibiting NCOA4-mediated ferritinophagy, the selective autophagy of ferritin for iron release. This degradation limits excessive lysosomal breakdown of iron-stored ferritin, preventing overload of the labile iron pool (LIP). HERC2's regulation integrates with feedback loops involving VAMP8, which mediates autophagosome-lysosome fusion essential for ferritinophagy completion; under iron-replete states, reduced NCOA4 activity dampens this process, maintaining iron balance. These actions form a bidirectional regulatory network where low iron promotes uptake and ferritin synthesis repression (via IRP2), while high iron curbs release from stores.^[44] Deficiency in HERC2, as observed in knockout models, disrupts this balance, leading to stabilization of both FBXL5 and NCOA4. Elevated FBXL5 reduces IRP2 levels, impairing TFRC-mediated uptake, while persistent NCOA4 drives aberrant ferritin recruitment to autophagosomes; however, impaired fusion (linked to downstream effects like reduced VAMP8) results in inefficient degradation and accumulation of free iron in the LIP. This dysregulation causes iron accumulation, heightened oxidative stress through reactive oxygen species (ROS) generation, and increased sensitivity to ferroptosis, with notable impacts in hepatic contexts where iron overload exacerbates hepatocyte damage and liver dysfunction.^[44]^[43]

Other Cellular Roles

HERC2 promotes the oligomerization of the tumor suppressor protein p53 through direct interaction via its CPH domain and p53's tetramerization domain, independent of HERC2's ubiquitin ligase activity.^[45] This interaction enhances p53's transcriptional activation of target genes such as p21 and p53R2, thereby modulating cellular responses including apoptosis thresholds without altering p53 protein stability.^[45] Depletion of HERC2 reduces p53 tetramer formation and transcriptional output, leading to increased cell proliferation and diminished DNA damage-induced responses.^[45] In p53 contexts, this mechanism supports DNA repair pathways by facilitating p53-dependent gene expression during genotoxic stress.^[45] Beyond p53 regulation, HERC2 contributes to endosomal trafficking processes, influencing the sorting, recycling, and degradation of membrane-associated proteins.^[22] It forms part of a complex with NEURL4 and LRRK2, which controls endosomal vesicular dynamics and cargo handling in the cytoplasm.^[22] Proteomic analyses have linked HERC2 to intracellular protein trafficking networks, suggesting its E3 ligase activity ubiquitinates substrates destined for endolysosomal pathways.^[46] HERC2 exhibits potential roles in antiviral defense by interacting with viral proteins, such as the E6 oncoprotein from human papillomavirus type 16 (HPV16).^[47] This association, identified through affinity purification, positions HERC2 as a possible E3 ligase that ubiquitinates viral components, thereby restricting viral replication or modulating infected cell responses, though direct ubiquitination remains to be fully characterized.^[47] Emerging research from the 2020s highlights HERC2's involvement in autophagy modulation via regulation of the selective autophagy receptor NCOA4, which interacts with LC3 to mediate ferritinophagy.^[27] Under iron-replete conditions, HERC2 binds the iron-sulfur cluster-laden HBD domain of NCOA4 using its CPH and INBD domains, promoting NCOA4 ubiquitination and proteasomal degradation to suppress autophagic flux.^[27] HERC2 deficiency elevates NCOA4 levels, enhancing LC3-associated ferritin degradation and altering cellular iron homeostasis.^[48] Additionally, HERC2 interacts with USP20 to indirectly influence ULK1 stability, further dysregulating autophagosome formation in deficient states.^[48]

Molecular Interactions

Known Binding Partners

HERC2 physically interacts with the deubiquitinase USP20, as demonstrated by endogenous co-immunoprecipitation in human cell lines. This binding enables HERC2 to ubiquitinate USP20 via its HECT domain, thereby modulating USP20 stability and activity under normal conditions, with dissociation occurring upon DNA damage-induced phosphorylation of USP20 to stabilize the deubiquitinase.^[37] HERC2 associates with the E3 ubiquitin ligase RNF8 in response to ionizing radiation, forming a complex at DNA damage foci on chromosomes. The interaction is mediated by phosphorylation of HERC2 at threonine 4827, which binds the forkhead-associated (FHA) domain of RNF8, facilitating ubiquitin chain assembly; this association is further promoted by DNA damage-inducible SUMOylation of HERC2.^[36] HERC2 binds the nucleotide excision repair (NER) protein XPA, promoting its ubiquitination and degradation to regulate NER efficiency. Phosphorylation of XPA at serine 196 by ATR kinase disrupts this interaction, stabilizing XPA and enhancing its retention at sites of ultraviolet-induced damage for NER complex assembly.^[49]^[50] HERC2 interacts with BRCA1, primarily through its HECT domain binding the BRCA1 degron, as confirmed by co-immunoprecipitation, leading to BRCA1 ubiquitination and cell cycle-dependent degradation. Similarly, HERC2 associates with Claspin in a BRCA1-dependent manner, verified by co-immunoprecipitation in human cells, to influence replication processes.^[39]^[51] HERC2 interacts with the tumor suppressor p53 through its CPH domain, promoting p53 oligomerization and enhancing its transcriptional activity, as shown by co-immunoprecipitation and reporter assays in human cells. This interaction supports p53-mediated tumor suppression without direct ubiquitination of p53.^[52]

Functional Interaction Networks

HERC2 integrates deeply into the ubiquitin-proteasome system (UPS) networks as a HECT-type E3 ubiquitin ligase, functioning as a hub that coordinates sequential ubiquitination cascades involving multiple ligases and regulatory enzymes. It promotes the degradation of UPS substrates by associating with other E3s like UBE3A and deubiquitinases such as USP33 and FBXL5, thereby modulating their stability and activity to maintain proteostasis. Proteomic screens have mapped over 280 high-confidence interactors, with quantitative metrics like normalized weighted D-scores indicating robust connections, such as UBE3A (NWD = 6.39) and multiple proteasome subunits, highlighting HERC2's centrality in proteasomal targeting pathways.^[53]^[46]^[22] Within the DNA damage response (DDR) network, HERC2 orchestrates ubiquitin-dependent signaling that assembles repair complexes at lesion sites, acting as a scaffold for RNF8-Ubc13 conjugation to amplify histone ubiquitination and factor retention. ATR-mediated phosphorylation of HERC2 enhances these events, while its regulation of USP20 stabilizes CLASPIN to propagate the Chk1 checkpoint signal, thereby bridging damage sensing to cell cycle arrest. This cascade supports downstream homologous recombination (HR) processes, intersecting with ubiquitin modifications in Fanconi anemia pathways that resolve interstrand crosslinks via HR. Proteomics from STRING database assign high-confidence scores (>0.9) to HERC2's links with DDR effectors like RNF8 and BRCA1, quantifying its networked influence.^[35]^[36]^[54]^[55]^[56]

Clinical Relevance

Associated Disorders

Deletions encompassing the HERC2 locus on chromosome 15q11-13 are part of the genomic region associated with Angelman syndrome, a neurodevelopmental disorder characterized by severe intellectual disability, ataxia, seizures, and inappropriate laughter. These deletions often include multiple genes, primarily affecting UBE3A.^[57] Independent biallelic mutations in HERC2 have been identified in patients with an Angelman-like syndrome, featuring global developmental delay, hypotonia, and epilepsy, underscoring HERC2's role in neurodevelopment.^[29]^[41] Rare variants in HERC2, particularly homozygous missense mutations, have been linked to autism spectrum disorders, often presenting with autistic behaviors, gait instability, and cognitive impairment. These variants disrupt HERC2's ubiquitin-mediated regulation of synaptic proteins, affecting neurodevelopmental pathways.^[58] HERC2 plays a role in DNA repair mechanisms. In uveal melanoma, common variants in the HERC2-OCA2 locus that influence pigmentation serve as risk factors, with lighter pigmentation associated with increased susceptibility.^[59] In colorectal cancer, frameshift mutations in HERC2 have been observed in microsatellite instability-high tumors, and HERC2 participates in ubiquitin-dependent DNA repair assembly, including BRCA1 retention at damage sites.^[35]^[60] HERC2 interacts with p53 to regulate its oligomerization and enhance transcriptional activity.^[52] HERC2 dysregulation has been implicated in hepatocellular carcinoma progression by promoting inflammation-driven stemness via STAT3 activation.^[4] Certain common variants in HERC2 are associated with benign pigmentation traits, such as blue eye color, without pathological consequences.^[59]

Genetic Variants and Polymorphisms

The HERC2 gene harbors several genetic variants, including the common single nucleotide polymorphism (SNP) rs12913832 (A/G), located in intron 86. This SNP is a key regulator of OCA2 expression and is strongly associated with blue versus brown eye color, with the G allele promoting reduced OCA2 transcription and lighter iris pigmentation. In European populations, the G allele frequency is approximately 80%, as derived from data in the 1000 Genomes Project, contributing significantly to the prevalence of blue eyes in these groups.^[61]^[62] Pathogenic variants in HERC2 are rare but have been linked to neurodevelopmental disorders, including autosomal recessive intellectual developmental disorder 38 (MIM 615516). A notable example is a homozygous frameshift mutation in exon 40, c.13767_13770delTGAA, resulting in p.(Asn4589Lysfs*10), which introduces a premature stop codon and leads to complete loss of HERC2 protein function. This variant has been identified in consanguineous families and is associated with severe developmental delays, including profound intellectual disability and early lethality. Other loss-of-function variants, such as missense mutations p.Pro594Leu and p.Arg1542His, cause milder phenotypes resembling Angelman syndrome, with global developmental delay and autism spectrum disorder features.^[5] Copy number variations (CNVs) affecting the HERC2 locus on chromosome 15q13.1 have been reported in neurodevelopmental contexts. A homozygous 286 kb deletion encompassing HERC2 and the adjacent OCA2 gene results in severe developmental delay, hypotonia, and visual impairment due to disrupted ubiquitination and pigmentation pathways. Broader CNVs in the 15q13 region, including deletions or duplications overlapping HERC2, are implicated in increased risk for epilepsy and schizophrenia, with haploinsufficiency contributing to synaptic dysfunction and neuropsychiatric outcomes.^[63]^[64] Haplotype block structure and linkage disequilibrium (LD) patterns around HERC2, particularly in the OCA2-HERC2 region, show population-specific variation as cataloged in the 1000 Genomes Project. In Europeans, strong LD (r² > 0.8) exists between rs12913832 and nearby SNPs like rs1129038, forming a haplotype block approximately 20-30 kb upstream of OCA2 that influences pigmentation traits. Global analyses reveal diverse LD decay rates, with shorter blocks in African populations (average ~5-10 kb) compared to longer ones in East Asians and Europeans (~15-25 kb), reflecting historical selection pressures on pigmentation loci. These patterns facilitate fine-mapping of causal variants in association studies.^[65]^[62]

Evolutionary Perspectives

Sequence Conservation

The HERC2 protein demonstrates remarkable sequence conservation across vertebrate species, particularly within its core functional domains. The HECT domain, responsible for ubiquitin transferase activity, and the RCC1-like domains (RLDs), which contribute to substrate recognition and guanine nucleotide exchange, exhibit greater than 90% amino acid identity among vertebrates, including between human and mouse orthologs. This high conservation reflects the indispensable role of these domains in E3 ubiquitin ligase function. In contrast, non-coding regions of the HERC2 gene show substantially lower sequence identity, allowing for species-specific regulatory adaptations while maintaining protein-coding integrity.^[66]^[67] HERC2 orthologs are identifiable throughout eukaryotic lineages, underscoring the ancient origins of the HERC family within the broader HECT E3 ligase superfamily. The HECT domain is conserved across all eukaryotes, with representatives such as the Tom1 protein in yeast (Saccharomyces cerevisiae) sharing structural and functional homology in ubiquitin conjugation pathways. In invertebrates, a clear ortholog exists in Drosophila melanogaster (termed herc2), which displays approximately 70% amino acid identity to the human HERC2 C-terminal region, encompassing the HECT and RLD domains. This indicates that the core architecture of HERC2 emerged early in metazoan evolution.^[68]^[14]^[69] Multiple sequence alignments of HERC2 orthologs reveal that key residues essential for ligase activity, including the catalytic cysteine in the HECT domain's active site, have been preserved since the last common ancestor of bilaterians, approximately 550-600 million years ago. Such deep-time conservation emphasizes the evolutionary pressure to maintain HERC2's role in protein ubiquitination and cellular homeostasis. Functional divergence is evident in mammals, where lineage-specific sequence expansions and domain acquisitions in HERC2 contribute to specialized regulatory interactions, notably in pigmentation control pathways.^[70]^[14]

Population Genetics and Adaptations

The blue-eye-associated variant rs12913832 in HERC2 arose as a founder mutation approximately 6,000–10,000 years ago, with haplotype analysis revealing a single shared haplotype across diverse blue-eyed individuals worldwide, indicating a common origin likely in the Black Sea region. This mutation, located in an enhancer element within an intron of HERC2, reduces expression of the adjacent OCA2 gene, leading to decreased melanin production in the iris. The restricted haplotype diversity supports a strong founder effect, as the derived G allele at this SNP is nearly identical in structure among carriers from various populations. The rs12913832 variant has experienced positive selection in European populations, driven by advantages in low-UV environments where lighter pigmentation facilitates vitamin D synthesis by allowing greater UVB penetration into the skin. This selection pressure is evident from ancient DNA analyses showing rapid allele frequency increases for pigmentation-lightening variants, including rs12913832, during the Neolithic and Bronze Age transitions in West Eurasia. Recent 2020s studies using large ancient DNA datasets confirm signatures of directional selection on HERC2/OCA2 loci, linking the spread of the derived allele to adaptations for depigmentation that enhanced survival in northern latitudes with reduced sunlight. Geographic clines in rs12913832 allele frequencies reflect these adaptive dynamics, with the derived G allele (associated with blue eyes and lighter skin) reaching frequencies of 70–90% in European populations but remaining rare or absent in African (0–5%) and East Asian (0–2%) groups. This stark differentiation underscores the variant's recent evolutionary fixation in northern latitudes, contrasting with the ancestral A allele's persistence in equatorial regions where darker pigmentation provides UV protection.

References

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HERC2 Gene - GeneCards | HERC2 Protein | HERC2 Antibody
Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ...
[2]
https://www.omim.org/entry/605837
[3]
E3 ubiquitin-protein ligase HERC2 - Homo sapiens (Human) - UniProt
Oct 5, 2010 · E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes.
[4]
HERC2 HECT and RLD domain containing E3 ubiquitin ... - NCBI
Sep 14, 2025 · HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway. Common genetic ...
[5]
Novel loss-of-function mutation in HERC2 is associated with severe ...
The HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial ...
[6]
A very large protein with diverse functional motifs is deficient in rjs ...
We have identified this adjacent gene, previously named rjs (runty jerky sterile), by positional cloning. The rjs cDNA is very large, covering 15,264 ...
[7]
p619, a giant protein related to the chromosome ... - PubMed
HERC1 protein, human; Ubiquitin-Protein Ligases; GTP-Binding Proteins; ADP-Ribosylation Factor 1; ADP-Ribosylation Factors. Associated data.
[8]
Ancestral Gene for Transcribed, Low-Copy Repeats in the Prader ...
Therefore, we first cloned the single-copy mouse Herc2 ortholog (Fig. 2a) to provide a guideline for isolation of 3′ human HERC2 cDNA sequences. The mouse ...
[9]
A Single SNP in an Evolutionary Conserved Region within Intron 86 ...
We screened an additional 92 SNPs in 300–3000 European individuals and found that a single SNP in intron 86 of HERC2, rs12913832, predicted eye color ...Missing: discovery | Show results with:discovery
[10]
Mammalian HECT ubiquitin-protein ligases - ScienceDirect.com
In the late 1990s, it was shown that the so-called rjs (runty, jerky, sterile) or jdf2 (juvenile development and fertility-2) mice harbor mutations in the Herc2 ...
[11]
Structure of the Highly Conserved HERC2 Gene and of Multiple ...
Our previous studies demonstrated that the human and mouse HERC2 cDNAs show an extraordinary 96% amino acid sequence identity (Ji et al. 1999). We extended this ...
[12]
https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02609-0
[13]
https://accscience.com/journal/AN/articles/online_first/5328
[14]
Herc2 MGI Mouse Gene Detail - MGI:103234 - HECT and RLD ...
Homozygotes for null mutations exhibit runting, nervousness, and incoordination. Males are sterile with sperm abnormalities, while females show reduced ...Missing: ruby- shaky
[15]
Functional and pathological relevance of HERC family proteins
HERC2. In the late 1990s, HERC2 was identified as the gene responsible for a syndrome in mice known as runty, jerky, sterile (rjs) or juvenile development ...
[16]
The HERC2 ubiquitin ligase is essential for embryonic development ...
Abstract. A mutation in the HERC2 gene has been linked to a severe neurodevelopmental disorder with similarities to the Angelman syndrome.Missing: ruby- 1990
[17]
Regulation of the MDM2‐p53 pathway by the ubiquitin ligase HERC2
Oct 30, 2019 · We report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its ...3.1 Mdm2 Binds Herc2 Through... · 3.2 Herc2 Regulates Mdm2... · 3.5 Stable Herc2...
[18]
Structural Insight into Binding of the ZZ Domain of HERC2 to Histone ...
Nov 3, 2020 · HERC2 is a large, 4,834-residue protein that contains the catalytic E3 ubiquitin ligase HECT domain, three RCC1-like domains (RLD) essential in ...
[19]
HERCing: Structural and Functional Relevance of the Large HERC ...
Aug 6, 2019 · Recessive mutations in the HERC2 locus are related to symptoms ranging from cognitive delay, ataxia, speech disorders, microcephalia, seizures, ...
[20]
The disordered negatively charged C‐terminus of the large HECT ...
Nov 20, 2024 · ... catalytic cysteine (C4762) is responsible for HERC2‐dependent ubiquitylation. Adjoining to the HERC2 HECT domain is a unique negatively ...
[21]
HERC2 protein expression summary
The RNA data was used to cluster genes according to their expression across tissues. Clusters contain genes that have similar expression patterns, and each ...
[22]
HERC2 inactivation abrogates nucleolar localization of RecQ ...
Jan 11, 2021 · HERC2, BLM and WRN localizes at the fibrillar center of the nucleolus. HERC2 has been previously reported to co-localize at the replication fork ...
[23]
605837 - HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2 - OMIM
... (runty, jerky, sterile) mice. Proc. Nat. Acad. Sci. 95: 9436-9441, 1998. [PubMed: 9689098, images, related citations] [Full Text]. Lyon, M. F., King, T. R. ...<|control11|><|separator|>
[24]
Mechanistic insights into the iron–sulfur cluster-dependent ... - PNAS
Jul 24, 2025 · Interestingly, the refined complex structure consists of two HERC2(2540-2700) molecules and one antiparallel NCOA4(395-442) dimer, forming a ...Sign Up For Pnas Alerts · Results · Both Herc2 Cph/ncoa4 And...
[25]
HERC2 regulates RPA2 by mediating ATR-induced Ser33 ... - Nature
Oct 3, 2019 · HERC2 E3 ligase activity could be inhibited by auto-ubiquitination and oligomerization, the mechanism shared by large HECT E3 ligases, and ...
[26]
Mutation of HERC2 causes developmental delay with Angelman-like ...
We establish that the encoded mutant HERC2 protein has a reduced half-life compared with its wild-type counterpart, which is associated with a significant ...
[27]
Showing Protein E3 ubiquitin-protein ligase HERC2 (HMDBP08656)
Showing Protein E3 ubiquitin-protein ligase HERC2 (HMDBP08656) ... Theoretical pI, 6.22. Pfam Domain Function. ZZ (PF00569 ); Cyt-b5 (PF00173 ) ...
[28]
HERC2 Gene - Ma'ayan Laboratory, Computational Systems Biology
In addition, HERC2 has a critical role in tumor suppression through its interaction with p53, where it facilitates p53 oligomerization and thus enhances its ...
[29]
HERC2 rs12913832 modulates human pigmentation by attenuating ...
Here we demonstrate that the HERC2 rs12913832 region functions as an enhancer regulating OCA2 transcription. In darkly pigmented human melanocytes carrying the ...
[30]
The common occurrence of epistasis in the determination of human ...
... HERC2 and SLC24A4 and revealed a new interaction between HERC2 and TYRP1 in the determination of eye colour in humans [38]. Here we further investigated ...
[31]
Direct evidence for positive selection of skin, hair, and eye ... - PNAS
Mar 10, 2014 · The high selection coefficients estimated for pigmentation genes HERC2 ... TYRP1, which are also implicated in the lightening of skin ...
[32]
HERC2 coordinates ubiquitin-dependent assembly of DNA repair ...
Here, we identify HERC2 as a factor that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes.Missing: TYRP1 stability
[33]
DNA damage–inducible SUMOylation of HERC2 promotes RNF8 ...
Apr 16, 2012 · SUMOylation of the ubiquitin ligase HERC2 promotes efficient chromatin licensing in the vicinity of DNA double-strand breaks.
[34]
HERC2-USP20 axis regulates DNA damage checkpoint through ...
Oct 29, 2014 · The DNA damage response triggers cell-cycle checkpoints, DNA repair and apoptosis using multiple post-translational modifications as ...
[35]
Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair - Oncogene
### Summary of XPA Regulation by HERC2 and ATR in NER
[36]
HERC2 is an E3 ligase that targets BRCA1 for degradation - PubMed
Aug 1, 2010 · Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation.
[37]
Complete loss of function of the ubiquitin ligase HERC2 causes a ...
HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation.
[38]
The HERC2 ubiquitin ligase is essential for embryonic development ...
Aug 30, 2016 · A mutation in the HERC2 gene has been linked to a severe neurodevelopmental disorder with similarities to the Angelman syndrome.Missing: expression gametogenesis
[39]
https://pubmed.ncbi.nlm.nih.gov/20631078/
[40]
https://pubmed.ncbi.nlm.nih.gov/27759030/
[41]
https://pubmed.ncbi.nlm.nih.gov/27528230/
[42]
The E3 Ubiquitin Protein Ligase HERC2 Modulates the Activity of ...
Results: HERC2 binds p53 and regulates its transcriptional activity, affecting cellular processes modulated by p53 such as cell growth or DNA damage response.Missing: biophysical | Show results with:biophysical
[43]
Proteomic Analysis and Identification of Cellular Interactors of the ...
(16, 17) E6AP was the first mammalian E3 ubiquitin ligase to be identified, and its association with the human papillomavirus (HPV) oncoprotein E6 was shown ...
[44]
The Ubiquitin-Specific Peptidase USP15 Regulates Human ...
In addition to the well-characterized E6AP ubiquitin-protein ligase, a second HECT domain protein (HERC2) and a deubiquitylating enzyme (USP15) were identified ...
[45]
Autophagy dysregulation via the USP20-ULK1 axis in the HERC2 ...
Apr 3, 2024 · The results confirmed the interaction between HERC2 and USP20 proteins. No interaction was detected between HERC2 and LC3 proteins (Fig. 6A) ...
[46]
Coordinated regulation of XPA stability by ATR and HERC2 during ...
Jan 2, 2014 · Here we show that ATR-mediated XPA phosphorylation enhances XPA stability by inhibiting HERC2-mediated ubiquitination and subsequent degradation.
[47]
Circadian control of XPA and excision repair of cisplatin-DNA ...
Mar 16, 2010 · Importantly, downregulation of HERC2 leads to stabilization of XPA and increased repair activity of cisplatin damage in cultured cells.
[48]
HERC2 Interacts with Claspin and Regulates DNA Origin Firing and ...
Because BRCA1 interacts with Claspin and acts as a second regulator of Chk1 activation (10), HERC2 may interact with Claspin and regulate DNA replication.
[49]
Proteomic Analysis and Identification of Cellular Interactors of the ...
NEURL4 and HERC2 were identified as interactors of the centrosomal protein CP110, and their binding is required for maintenance of centrosome integrity. E6AP ...
[50]
HERC2-USP20 axis regulates DNA damage checkpoint through ...
Oct 29, 2014 · ... HERC2 resulted in upregulation of USP20 levels and protein stability. These results suggest that HERC2 might be an E3 ubiquitin ligase of USP20.
[51]
Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin ...
Mar 31, 2021 · In this review, we focus on the molecular mechanisms and interactions that occur between p53, the HECT E3 ubiquitin ligases WWP1, SMURF1, HECW1 and HERC2.
[52]
HERC2 protein (human) - STRING interaction network
Browse STRING ; number of nodes: 11 ; number of edges: 19 ; average node degree: 3.45 ; avg. local clustering coefficient: 0.845 ; expected number of edges: 11.
[53]
Interactions Between HERC2, OCA2 and MC1R May Influence ...
Feb 17, 2009 · Recent studies have revealed that interactive effects between HERC2 and OCA2 may be responsible for blue eye colour determination in humans.
[54]
Interactions between HERC2, OCA2 and MC1R may ... - PubMed
HERC2 and OCA2 interactions may affect blue eye color. HERC2 is linked to skin/hair color. MC1R interacts with HERC2 in skin/hair color. OCA2 is linked to eye ...Missing: regulatory network
[55]
Structure of the highly conserved HERC2 gene and of multiple ...
We have now constructed and sequenced a genomic contig of HERC2, revealing a total of 93 exons spanning approximately 250 kb and a CpG island promoter. A ...
[56]
A homozygous missense mutation in HERC2 associated with global ...
... Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait ...
[57]
Proteomic analysis and identification of cellular interactors ... - PubMed
Feb 6, 2015 · Mutations in HERC2 are linked to developmental delays and impairment caused by nervous system dysfunction, such as Angelman Syndrome and autism ...
[58]
Genetic markers of pigmentation are novel risk loci for uveal ...
Aug 8, 2016 · Genetic markers of pigmentation are novel risk loci for uveal melanoma ... HERC2/OCA2, which determines eye-color in the human population.
[59]
Pharmacological inhibition of BAP1 recruits HERC2 to competitively ...
Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.<|control11|><|separator|>
[60]
The E3 ubiquitin protein ligase HERC2 modulates the activity of ...
May 23, 2014 · Through this interaction, HERC2 regulates p53 activity. RNA interference experiments showed how HERC2 depletion reduces the transcriptional ...Missing: UV | Show results with:UV
[61]
Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
MDM2 and p53 are regulated by a negative feedback loop. HERC2 modulates p53 oligomerization and forms a complex with MDM2, p53, and NEURL4. HERC2 knockdown ...
[62]
Three Genome-wide Association Studies and a Linkage Analysis ...
... HERC2 shows association to iris color independent of OCA2. This finding is in line with the LD patterns in the GWA-ERF250K and the GWA-Rdam500K data sets (LD ...
[63]
Further insight into the global variability of the OCA2-HERC2 locus ...
Nov 18, 2021 · One SNP in particular, rs12913832 in HERC2, is responsible for the greatest proportion of eye color predictability, this SNP together with five ...
[64]
Complete loss of function of the ubiquitin ligase HERC2 causes a ...
Oct 19, 2016 · HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation.<|control11|><|separator|>
[65]
Duplication Versus Deletion Through the Lens of 15q13.3 - NIH
Nov 12, 2022 · Such copy number variants (CNVs) can involve either duplication or deletion of susceptible portions of the human genome, while these frequently ...
[66]
A global view of the OCA2-HERC2 region and pigmentation
Nov 8, 2011 · OCA2 encodes the protein P, a transmembrane protein, and has been shown to play a role in pigmentation in both humans and mice (Frudakis et al.
[67]
HERC2 - an overview | ScienceDirect Topics
HERC2 has an important role in cell cycle regulation, development of embryonic neuronal and muscle function, mitochondrial function, DNA repair, motor ...
[68]
Herc2 HECT and RLD domain containing E3 ubiquitin protein ligase ...
HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress. identified HERC2, a HECT domain ...
[69]
A Genomic Survey of HECT Ubiquitin Ligases in Eukaryotes ... - PMC
There is indirect evidence that Tom1 (a yeast HUWE1-like protein) intervenes in Cdc6 posttranslational regulation (Hall et al. 2007). UPL1/2 is a ...
[70]
https://www.immunologyresearchjournal.com/articles/a-short-evolutionary-journey-across-the-herc-ubiquitin-ligases.html
[71]
A short evolutionary journey across the HERC Ubiquitin Ligases
Feb 5, 2018 · In the present minireview, we will attempt to shortly summarize and revise the long evolutionary history of the HERC E3 ubiquitin ligases members.