Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response

Cellular homeostasis is governed by the precise expression of genes that control the translation, localization, and termination of proteins. Oftentimes, environmental and biological factors can introduce mutations into the genetic framework of cells during their growth and division, and these genetic abnormalities can result in malignant transformations caused by protein malfunction. For example, p53 is a prominent tumor suppressor protein that is capable of undergoing more than 300 posttranslational modifications (PTMs) and is involved with controlling apoptotic signaling, transcription, and the DNA damage response (DDR). 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, and other oncogenic proteins in the cell to explore how irregular HECT-p53 interactions can induce tumorigenesis.

• Publication year

  2021

• Venue

  Frontiers in Oncology

• Publication date

  2021-03-31

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fonc.2021.659049PMID 33869064PMCID 8044464
• 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.

• Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

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

  2020cited by this paper
• The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

  2020cited by this paper
• Oncogenic Smurf1 promotes PTEN wild-type glioblastoma growth by mediating PTEN ubiquitylation

  2020cited by this paper
• miR‐4319 inhibited the development of thyroid cancer by modulating FUS‐stabilized SMURF1

  2020cited by this paper
• Phosphorylation Control of p53 DNA-Binding Cooperativity Balances Tumorigenesis and Aging

  2020cited by this paper
• E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma

  2020cited by this paper
• The Role of Ubiquitination and SUMOylation in DNA Replication.

  2020cited by this paper
• STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer

  2020cited by this paper
• HECT E3 ubiquitin ligases – emerging insights into their biological roles and disease relevance

  2020cited by this paper
• Alternative Mechanisms of mRNA Translation Initiation in Cellular Stress Response and Cancer.

  2019cited by this paper
• A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases

  2019cited by this paper
• E6AP Promotes a Metastatic Phenotype in Prostate Cancer

  2019cited by this paper
• HECT E3 Ligases: A Tale With Multiple Facets

  2019cited by this paper
• SMURF1-mediated ubiquitination of ARHGAP26 promotes ovarian cancer cell invasion and migration

  2019cited by this paper
• Genome-wide identification of genes encoding putative secreted E3 ubiquitin ligases and functional characterization of PbRING1 in the biotrophic protist Plasmodiophora brassicae

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

  2019influential reference
• Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms

  2019cited by this paper
• Stepwise multipolyubiquitination of p53 by the E6AP-E6 ubiquitin ligase complex

  2019cited by this paper
• Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome

  2018cited by this paper
• Ubiquitin System

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

  2018cited by this paper
• Structural dynamics of the E6AP/UBE3A-E6-p53 enzyme-substrate complex

  2018cited by this paper
• ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response

  2018cited by this paper
• High expression of WWP1 predicts poor prognosis and associates with tumor progression in human colorectal cancer.

  2018cited by this paper
• Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes.

  2018cited by this paper
• Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIγ

  2017cited by this paper
• The emerging roles of the ubiquitination/deubiquitination system in tumor radioresistance regarding DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties: Insight into the development of novel radiosensitizing strategies.

  2017cited by this paper
• Reciprocal regulation between βTrCP and Smurf1 suppresses proliferative capacity of liver cancer cells

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

  2017influential reference
• SMURF1 promotes the proliferation, migration and invasion of gastric cancer cells.

  2017cited by this paper
• Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER

  2017cited by this paper
• Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer

  2017influential reference
• Ubiquitin Ligases: Structure, Function, and Regulation.

  2017cited by this paper
• Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity

  2017cited by this paper
• Molecular basis of interactions between SH3 domain-containing proteins and the proline-rich region of the ubiquitin ligase Itch

  2017cited by this paper
• E6AP promotes prostate cancer by reducing p27 expression

  2017cited by this paper
• ASPP2 suppresses invasion and TGF-β1-induced epithelial-mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer.

  2017influential reference
• Structural mechanisms of HECT-type ubiquitin ligases

  2017cited by this paper
• Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non–small cell lung cancer

  2017cited by this paper
• Structural Studies of the Nedd4 WW Domains and Their Selectivity for the Connexin43 (Cx43) Carboxyl Terminus*

  2016cited by this paper
• Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells

  2016cited by this paper
• System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.

  2016cited by this paper
• Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.

  2016cited by this paper
• Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

  2016cited by this paper
• Ubiquitination as a Mechanism To Transport Soluble Mycobacterial and Eukaryotic Proteins to Exosomes

  2015cited by this paper
• Intracellular Analysis of the Interaction between the Human Papillomavirus Type 16 E6 Oncoprotein and Inhibitory Peptides

  2015cited by this paper
• Knockdown of WWP1 inhibits growth and invasion, but induces apoptosis of osteosarcoma cells.

  2015cited by this paper
• The Cellular Response to Oxidatively Induced DNA Damage and Polymorphism of Some DNA Repair Genes Associated with Clinicopathological Features of Bladder Cancer

  2015cited by this paper
• Nedd4L expression is decreased in ovarian epithelial cancer tissues compared to ovarian non‐cancer tissue

  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
• ATM and ATR as therapeutic targets in cancer.

  2015cited by this paper
• A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases.

  2015cited by this paper
• SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis.

  2015cited by this paper
• The E3 ubiquitin ligase Itch and Yap1 have antagonistic roles in the regulation of ASPP2 protein stability

  2015cited by this paper
• Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53

  2015cited by this paper
• Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53

  2015cited by this paper
• Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10

  2014cited by this paper
• New insights into ubiquitin E3 ligase mechanism

  2014cited by this paper
• Human cytochrome b5 reductase: structure, function, and potential applications

  2014cited by this paper
• Bortezomib prevents oncogenesis and bone metastasis of prostate cancer by inhibiting WWP1, Smurf1 and Smurf2.

  2014cited by this paper
• Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase

  2014cited by this paper
• p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

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

  2014cited by this paper
• Stage of Breast Cancer Progression Influences Cellular Response to Activation of the WNT/Planar Cell Polarity Pathway

  2014cited by this paper
• RBR E3 ubiquitin ligases: new structures, new insights, new questions

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

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

  2014influential reference
• NEDD4L Is Downregulated in Colorectal Cancer and Inhibits Canonical WNT Signaling

  2013cited by this paper
• WWP1 E3 Ligase Targets LATS1 for Ubiquitin-Mediated Degradation in Breast Cancer Cells

  2013influential reference
• Cell cycle control across the eukaryotic kingdom.

  2013cited by this paper
• Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression.

  2013influential reference
• Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration

  2013cited by this paper
• WWP1 gene is a potential molecular target of human oral cancer.

  2013cited by this paper
• Identification of the NEDD4L Gene as a Prognostic Marker by Integrated Microarray Analysis of Copy Number and Gene Expression Profiling in Non-small Cell Lung Cancer

  2013cited by this paper
• Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

  2012cited by this paper
• p53 acetylation enhances Taxol-induced apoptosis in human cancer cells

  2012cited by this paper
• Post-translational modifications of p53 tumor suppressor: determinants of its functional targets.

  2012cited by this paper
• The cellular level of histone H3 lysine 4 dimethylation correlates with response to adjuvant gemcitabine in Japanese pancreatic cancer patients treated with surgery.

  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
• The emerging role of Polycomb repressors in the response to DNA damage

  2012cited by this paper
• Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer

  2012cited by this paper
• Knock down of p53 or its ubiquitin ligase E6AP does not affect the sensitivity of human papillomavirus-positive cervical cancer cells to cisplatin.

  2012cited by this paper
• Recognition mechanism of p63 by the E3 ligase Itch

  2012cited by this paper
• The ubiquitin code.

  2012cited by this paper
• The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage.

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

  2012cited by this paper
• Peptide Interactions Stabilize and Restructure Human Papillomavirus Type 16 E6 To Interact with p53

  2012cited by this paper
• Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways.

  2012cited by this paper
• The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer

  2012cited by this paper
• Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation

  2011cited by this paper
• Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity.

  2011cited by this paper
• A Smad action turnover switch operated by WW domain readers of a phosphoserine code.

  2011cited by this paper
• Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

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

  2011cited by this paper
• RNF43 interacts with NEDL1 and regulates p53-mediated transcription.

  2011influential reference
• Physical and Functional Interaction of the HECT Ubiquitin-protein Ligases E6AP and HERC2*

  2011cited by this paper
• Smad Ubiquitylation Regulatory Factor 1/2 (Smurf1/2) Promotes p53 Degradation by Stabilizing the E3 Ligase MDM2*

  2010influential reference
• Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity

  2010cited by this paper
• Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

  2010cited by this paper

• HERC2 as a Potential Biomarker for Prognosis and Response to Bevacizumab in Ovarian Cancer: A Bioinformatics Approach

  2025cites this paper
• [WW domain-containing ubiquitin E3 ligase 1 regulates immune infiltration in tumor microenvironment of ovarian cancer].

  2025cites this paper
• Progress in ubiquitination and hepatocellular carcinoma: a bibliometric analysis

  2025cites this paper
• NEDD4 signaling: a new frontier in the diagnosis and treatment of breast and ovarian cancers

  2025cites this paper
• Nedl1 knockout ameliorates cognitive impairment and improves epilepsy threshold in pilocarpine-induced epileptic mice

  2025cites this paper
• The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair

  2025cites this paper
• Survival in uveal melanoma patients is linked to genetic variation at HERC2 SNP rs12913832.

  2024cites this paper
• The Genetic Architecture of the Root System during Seedling Emergence in Populus euphratica under Salt Stress and Control Environments

  2024cites this paper
• Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder

  2024cites this paper
• Impact of genomic and epigenomic alterations of multigene on a multicancer pedigree

  2024cites this paper
• NEDD4L Suppresses Proliferation and Promotes Apoptosis by Ubiquitinating RAC2 Expression and Acts as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma

  2024cites this paper
• Stem cell models of Angelman syndrome

  2023cites this paper
• Redefining the catalytic HECT domain boundaries for the HECT E3 ubiquitin ligase family

  2022cites this paper
• The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

  2022cites this paper
• Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

  2021cites this paper
• Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers

  2021cites this paper