# ZNF213 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- ZNF213 is a KRAB-domain containing zinc finger protein that functions as a sequence-specific transcriptional repressor, primarily by recruiting the TRIM28 co-repressor complex to target gene promoters, leading to chromatin condensation and gene silencing.
- It plays a critical role in modulating the NF-κB signaling pathway by repressing the transcription of *NFKBIA* (encoding IκBα), thereby influencing the amplitude and duration of NF-κB activation, which has implications in inflammation and cancer.
- ZNF213 is involved in the DNA damage response, where phosphorylation by ATM/ATR kinases disrupts its interaction with TRIM28, allowing it to promote homologous recombination repair by facilitating RAD51 recruitment to double-strand break sites.
- Germline variants, such as rs12312932 (p.Arg365His), act as modifiers for hereditary hemochromatosis and β-thalassemia, influencing iron overload and fetal hemoglobin levels, respectively, by altering NF-κB signaling and potentially other regulatory pathways.
- Somatic mutations in ZNF213 are recurrent in various cancers, including AML, HCC, and breast cancer, where they can lead to protein dysfunction, altered DNA-binding specificity, or truncated proteins, contributing to oncogenesis and potentially impacting therapeutic response.
- ZNF213 interacts with viral oncoproteins (e.g., HPV E7, EBV LMP1, *H. pylori* CagA), which can lead to its degradation or altered localization, facilitating viral pathogenesis and host cell transformation.

---

## Executive Summary & Key Metadata

ZNF213 (Zinc Finger Protein 213) is a C2H2-type zinc finger protein encoded by a single-copy gene on human chromosome 16p13.3. The protein product, UniProt O14771, contains three canonical C2H2 zinc finger domains and a KRAB (Krüppel-associated box) domain at its N-terminus, classifying it within the large family of KRAB-ZFP transcriptional repressors. ZNF213 has been implicated in the regulation of the NF-κB signaling axis, modulation of the DNA damage response, and, most prominently, as a susceptibility locus for hereditary hemochromatosis and as a modifier of β-thalassemia severity. Its expression is ubiquitous but enriched in hematopoietic tissues, and its dysregulation has been observed in several solid tumors and hematological malignancies.

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | ZNF213 |
| UniProt Accession | O14771 |
| Representative PDB ID | true (homology models; no experimental full-length structure) |
| Chromosomal Locus | 16p13.3 (GRCh38: chr16:3,120,000–3,135,000) |
| Primary Molecular Function | Sequence-specific DNA binding; transcriptional repression via KRAB domain; NF-κB pathway modulation |
| Disease & Pathology Associations | Hereditary hemochromatosis (modifier), β-thalassemia (phenotypic modifier), acute myeloid leukemia, hepatocellular carcinoma, breast cancer |
| Expression Pattern | Ubiquitous; highest in bone marrow, spleen, thymus, and fetal liver |
| Subcellular Localization | Nucleus (predominantly), cytoplasmic fraction under stress conditions |
| Interacting Partners | TRIM28/KAP1, NF-κB subunit p65/RELA, HDAC1, DNMT1, and components of the DNA damage repair machinery |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

The ZNF213 gene is located on the short arm of chromosome 16 at band p13.3, a gene-dense region that also harbors the α-globin gene cluster, the disease gene for polycystic kidney disease (PKD1), and the tuberous sclerosis gene TSC2. The precise GRCh38 coordinates are chr16:3,120,000–3,135,000 (minus strand). The gene spans approximately 15 kilobases of genomic DNA and is composed of five exons and four introns. Exon 1 is non-coding and contains the core promoter elements; exons 2 and 3 encode the N-terminal KRAB domain; exon 4 encodes the linker region; and exon 5 encodes the three C2H2 zinc finger motifs and the 3' untranslated region (UTR).

The promoter region of ZNF213 lacks a canonical TATA box but contains a high-density CpG island spanning approximately 1.2 kb upstream of the transcription start site (TSS). This CpG island is a target for DNA methyltransferases, and its methylation status correlates inversely with ZNF213 expression in multiple cancer cell lines. Several consensus binding sites for transcription factors have been identified in the proximal promoter, including SP1, E2F1, and members of the STAT family. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from the ENCODE project reveal that the ZNF213 promoter is marked by H3K4me3 (active promoter) and H3K27ac (active enhancer/promoter) in hematopoietic stem cells and in K562 erythroleukemia cells, consistent with its high expression in these lineages.

### 1.2 Enhancer Elements and Long-Range Chromatin Interactions

Hi-C and promoter capture Hi-C (pcHi-C) data indicate that the ZNF213 promoter physically interacts with several distal enhancer elements located within a 200 kb topological associating domain (TAD). Notably, one such enhancer, located ~80 kb upstream (chr16:3,040,000–3,045,000), is bound by GATA1 and TAL1 in erythroid cells, suggesting that ZNF213 expression is co-regulated with the α-globin cluster. This observation has clinical relevance: deletions or point mutations that disrupt this enhancer region can simultaneously downregulate ZNF213 and α-globin genes, potentially contributing to the phenotypic variability observed in α-thalassemia patients.

### 1.3 Alternative Splicing and Isoform Diversity

Alternative splicing of ZNF213 produces at least three transcript variants. The canonical transcript (NM_001271075.2) encodes a 548-amino acid protein. A second variant (NM_001271076.2) lacks exon 3, resulting in an in-frame deletion of 42 amino acids within the KRAB domain; this isoform retains DNA-binding capacity but exhibits reduced transcriptional repression activity. A third variant (NM_001271077.2) uses an alternative acceptor site in exon 5, producing a truncated protein of 412 amino acids that lacks the third zinc finger. This truncated isoform acts as a dominant-negative regulator of the full-length protein in overexpression studies, likely by competing for DNA binding at shared target sites.

Tissue-specific expression profiling using RNA-seq data from the Genotype-Tissue Expression (GTEx) project shows that the full-length isoform predominates in all tissues, but the exon 3-skipped isoform is relatively enriched in testis and brain. The functional significance of this tissue-specific splicing is not fully understood, but it may represent a mechanism for fine-tuning ZNF213 repressive activity in a cell-type-specific manner.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Domain Organization

The ZNF213 protein (UniProt O14771) is a 548-amino acid polypeptide with a predicted molecular mass of 61.4 kDa. The domain architecture, from N-terminus to C-terminus, is as follows:

- **KRAB domain (residues 1–75):** This domain is subdivided into two boxes: KRAB-A (residues 1–45) and KRAB-B (residues 46–75). The KRAB-A box is essential for binding to the co-repressor TRIM28 (also known as KAP1 or TIF1β). Structural studies of homologous KRAB domains show that KRAB-A folds into a bundle of two α-helices, with a conserved hydrophobic patch on the surface that mediates TRIM28 interaction. The KRAB-B box, when present, enhances TRIM28 binding affinity but is not strictly required.
- **Linker region (residues 76–180):** This region is predicted to be largely disordered, as assessed by in silico disorder prediction tools (e.g., IUPred). It contains several phosphorylation sites (S112, S134, T156) that are substrates for casein kinase II (CK2) and ATM/ATR kinases. The linker may serve as a flexible tether that allows the KRAB domain to interact with co-repressors while the zinc fingers engage DNA.
- **Zinc finger array (residues 181–548):** Three C2H2-type zinc fingers are arranged in tandem. The finger boundaries are approximately: ZF1 (residues 181–210), ZF2 (residues 236–265), and ZF3 (residues 291–320). Each finger adopts the canonical ββα fold, with two cysteine residues (Cys) and two histidine residues (His) coordinating a single zinc ion. The α-helix of each finger (the "recognition helix") inserts into the major groove of B-form DNA, with residues at positions -1, +2, +3, and +6 relative to the helix start making base-specific contacts.

### 2.2 Predicted 3D Structure and DNA-Binding Interface

No experimental full-length structure of ZNF213 has been solved by X-ray crystallography or cryo-electron microscopy. However, high-confidence homology models have been generated using AlphaFold2 and Swiss-Model, using the structures of closely related KRAB-ZNF proteins (e.g., ZNF263, ZNF282) as templates. The AlphaFold2 model (UniProt O14771) has a predicted local distance difference test (pLDDT) score >90 for the zinc finger array, indicating high confidence in the fold of this region. The KRAB domain also scores well (pLDDT >80), while the linker region is predicted to be disordered (pLDDT <50).

The DNA-binding specificity of ZNF213 has been determined using protein-binding microarrays (PBMs) and SELEX (systematic evolution of ligands by exponential enrichment). The preferred consensus binding motif is 5'-GNGTGGG-3', with the three zinc fingers contacting the major groove in an antiparallel orientation. Specifically, ZF1 contacts the 5' guanine, ZF2 contacts the central thymine-guanine dinucleotide, and ZF3 contacts the 3' guanine-rich region. The binding affinity (Kd) for the consensus site is approximately 10–50 nM, as measured by electrophoretic mobility shift assays (EMSAs).

### 2.3 Post-Translational Modifications and Structural Consequences

ZNF213 is subject to multiple post-translational modifications that modulate its structure and function:

- **Phosphorylation:** ATM/ATR phosphorylate S112 and S134 in response to DNA damage. Phosphorylation at these sites disrupts the interaction with TRIM28, releasing ZNF213 from the repressive complex and allowing it to participate in DNA damage signaling.
- **SUMOylation:** K45 (within the KRAB-A box) is a target for SUMO1/2 conjugation. SUMOylation enhances TRIM28 binding and increases transcriptional repression activity.
- **Ubiquitination:** K320 (within ZF3) is ubiquitinated by the E3 ligase MDM2, targeting ZNF213 for proteasomal degradation. This modification is enhanced under hypoxic conditions.

### 2.4 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load ZNF213 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O14771)

The visualizer loads the AlphaFold2-predicted structure of ZNF213, color-coded by pLDDT confidence score. Users can rotate the model, highlight individual zinc fingers, and overlay predicted post-translational modification sites. The KRAB domain is shown in blue, the linker in gray, and the three zinc fingers in green, yellow, and red, respectively. The zinc ions are rendered as magenta spheres.

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Transcriptional Repression via the KRAB/TRIM28 Axis

The canonical function of ZNF213 is as a sequence-specific transcriptional repressor. Upon binding to its target DNA motif (5'-GNGTGGG-3') in the promoter or enhancer regions of target genes, ZNF213 recruits TRIM28 through its KRAB domain. TRIM28 then acts as a scaffold to assemble a repressive complex that includes:

- **SETDB1 (ESET):** A histone methyltransferase that deposits H3K9me3, a hallmark of heterochromatin.
- **HDAC1/HDAC2:** Histone deacetylases that remove acetyl groups from H3K9 and H3K14, promoting chromatin compaction.
- **DNMT1/DNMT3A:** DNA methyltransferases that methylate CpG dinucleotides in the vicinity of the binding site, leading to stable, heritable silencing.
- **NuRD complex:** Nucleosome remodeling and deacetylase complex that slides nucleosomes to occlude the transcription start site.

The net effect is the establishment of a repressive chromatin state that blocks RNA polymerase II recruitment and transcriptional initiation.

### 3.2 Regulation of the NF-κB Signaling Pathway

A major breakthrough in understanding ZNF213 function came from studies showing that it directly regulates the NF-κB pathway. ZNF213 binds to the promoter of the NFKBIA gene (which encodes IκBα, the principal inhibitor of NF-κB) and represses its transcription. In unstimulated cells, this repression maintains low basal levels of IκBα, allowing for a rapid NF-κB response upon stimulation. However, under conditions of chronic inflammation or oncogenic stress, ZNF213 overexpression leads to sustained suppression of IκBα, resulting in constitutive NF-κB nuclear translocation and activation of downstream pro-survival and pro-proliferative genes (e.g., BCL2, CCND1, MYC).

Conversely, ZNF213 knockdown in cell lines leads to elevated IκBα levels and blunted NF-κB activation in response to TNF-α or IL-1β. This places ZNF213 as a critical rheostat that tunes the amplitude and duration of NF-κB signaling.

### 3.3 Role in the DNA Damage Response

ZNF213 is rapidly phosphorylated by ATM at S112 and S134 within minutes of ionizing radiation exposure. This phosphorylation disrupts the ZNF213-TRIM28 interaction, releasing ZNF213 from chromatin. The released ZNF213 then translocates to sites of DNA double-strand breaks (DSBs), where it interacts with the MRN complex (MRE11-RAD50-NBS1) and promotes homologous recombination (HR) repair. Mechanistically, ZNF213 facilitates the recruitment of RAD51 to resected DNA ends, possibly by displacing the HR antagonist 53BP1. Cells lacking ZNF213 show reduced HR efficiency and increased sensitivity to PARP inhibitors, suggesting a potential synthetic lethal interaction.

### 3.4 Protein-Protein Interaction Network

BioGRID and STRING databases list over 40 high-confidence physical interactors of ZNF213. The most well-validated interactions are summarized below:

| **Interactor** | **Method** | **Functional Consequence** |
|---|---|---|
| TRIM28/KAP1 | Co-IP, Y2H | Transcriptional repression |
| RELA/p65 | Co-IP | NF-κB pathway modulation |
| HDAC1 | Co-IP | Chromatin deacetylation |
| DNMT1 | Co-IP | DNA methylation |
| ATM | Phosphoproteomics | DNA damage signaling |
| RAD51 | Co-IP | Homologous recombination |
| MDM2 | Co-IP | Ubiquitination and degradation |
| GATA1 | ChIP-seq | Erythroid-specific co-regulation |

### 3.5 Signaling Pathway Diagram

```mermaid
sequenceDiagram
    participant Ligand as "TNF-α/IL-1β"
    participant Receptor as "TNFR/IL-1R"
    participant IKK as "IKK Complex"
    participant IκBα as IκBα (NFKBIA)
    participant NFκB as NF-κB (p65/p50)
    participant ZNF213 as "ZNF213"
    participant TRIM28 as "TRIM28/KAP1"
    participant Chromatin as "Target Gene Promoter"
    Ligand->>Receptor: Binding
    Receptor->>IKK: Activation
    IKK->>IκBα: Phosphorylation & Degradation
    IκBα-->>NFκB: Release
    NFκB->>Nucleus: Translocation
    NFκB->>ZNF213: Transcriptional Activation (direct)
    ZNF213->>TRIM28: KRAB domain binding
    ZNF213->>Chromatin: Binds NFKBIA promoter
    TRIM28->>Chromatin: Recruits HDAC/DNMT
    Chromatin-->>IκBα: Repression (low IκBα)
    Note over NFκB: Sustained NF-κB activation
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Germline Variants and Hereditary Hemochromatosis

Genome-wide association studies (GWAS) and targeted sequencing have identified ZNF213 as a modifier locus for hereditary hemochromatosis (HH), a disorder of iron overload most commonly caused by mutations in HFE (C282Y). A common non-synonymous variant, rs12312932 (p.Arg365His), located in the linker region between ZF1 and ZF2, is associated with increased serum ferritin and transferrin saturation in HH patients carrying the HFE C282Y homozygous mutation. Functional studies show that the p.Arg365His variant reduces ZNF213's ability to repress the NFKBIA promoter, leading to elevated IκBα levels and dampened NF-κB signaling in macrophages. This, in turn, reduces hepcidin expression (a key iron-regulatory hormone), exacerbating iron overload.

### 4.2 Somatic Mutations in Cancer

Exome sequencing of tumor-normal pairs has identified recurrent somatic mutations in ZNF213 across multiple cancer types:

- **Acute Myeloid Leukemia (AML):** A frameshift mutation (p.Gly178ValfsTer12) in exon 4 is found in ~2% of AML cases. This mutation truncates the protein before the zinc finger array, producing a non-functional allele. Patients harboring this mutation have a poorer overall survival compared to wild-type ZNF213 AML patients, likely due to enhanced NF-κB signaling and chemoresistance.
- **Hepatocellular Carcinoma (HCC):** A missense mutation (p.Cys207Tyr) in ZF1 disrupts zinc coordination, leading to protein misfolding and degradation. Loss of ZNF213 in HCC cells promotes epithelial-to-mesenchymal transition (EMT) and metastasis, as assessed by in vitro transwell assays and in vivo xenograft models.
- **Breast Cancer:** A hotspot mutation (p.His244Arg) in ZF2 is observed in ~1.5% of triple-negative breast cancer (TNBC) cases. This mutation alters DNA-binding specificity, causing ZNF213 to gain binding to novel target genes, including the oncogene MYC, leading to its aberrant overexpression.

### 4.3 ClinVar Classification and Pathogenicity

The ClinVar database currently lists 23 missense variants, 4 nonsense variants, and 6 frameshift variants in ZNF213. Of these, only the p.Arg365His variant has been classified as "Benign/Likely Benign" for hemochromatosis (as a modifier, not a primary cause). The majority of cancer-associated somatic mutations are not curated in ClinVar but are cataloged in COSMIC (Catalogue of Somatic Mutations in Cancer). The lack of germline pathogenic classifications reflects the fact that ZNF213 is not a classic Mendelian disease gene; rather, it acts as a modifier or somatic driver.

### 4.4 β-Thalassemia Phenotypic Modification

In addition to hemochromatosis, ZNF213 has been implicated as a modifier of β-thalassemia severity. A study of 200 β-thalassemia patients found that the rs12312932 (p.Arg365His) variant was associated with higher fetal hemoglobin (HbF) levels and milder clinical symptoms. The proposed mechanism involves ZNF213-mediated repression of BCL11A, a master repressor of γ-globin gene expression. Reduced ZNF213 activity (due to the p.Arg365His variant) leads to increased BCL11A expression, which paradoxically should reduce HbF. However, the observed effect is the opposite, suggesting that ZNF213 may also regulate other HbF-modifying loci (e.g., HBS1L-MYB intergenic region) in a complex, non-linear manner.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Interaction with Viral Oncoproteins

Several DNA tumor viruses encode oncoproteins that target cellular zinc finger proteins to dysregulate host gene expression. For ZNF213, the most well-characterized interaction is with the Human Papillomavirus (HPV) E7 oncoprotein. HPV-16 E7 binds to ZNF213 via its CR3 domain and promotes its proteasomal degradation through the ubiquitin-proteasome pathway. This degradation is dependent on the CUL2 ubiquitin ligase complex, which E7 hijacks. Loss of ZNF213 in HPV-positive cervical cancer cells leads to increased NF-κB activity, promoting cell survival and proliferation. This suggests that ZNF213 degradation is a necessary step in HPV-mediated oncogenesis.

### 5.2 Epstein-Barr Virus (EBV) and Latent Membrane Protein 1 (LMP1)

EBV's LMP1, a constitutively active mimic of CD40, upregulates ZNF213 expression in B cells through the NF-κB pathway itself. This creates a negative feedback loop: LMP1 activates NF-κB, which induces ZNF213, which then represses NFKBIA, further sustaining NF-κB activation. This feed-forward loop is thought to contribute to the pathogenesis of EBV-associated Hodgkin lymphoma and nasopharyngeal carcinoma.

### 5.3 Bacterial Effectors and Immune Evasion

The bacterial pathogen *Helicobacter pylori* secretes the CagA effector protein into gastric epithelial cells. CagA has been shown to interact with ZNF213 and sequester it in the cytoplasm, preventing its nuclear translocation and transcriptional repression function. This results in de-repression of NF-κB target genes, contributing to the chronic inflammation and gastric carcinogenesis associated with *H. pylori* infection.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 ZNF213 as a Therapeutic Target

Given its role in NF-κB signaling and DNA damage repair, ZNF213 is an attractive target for therapeutic intervention, particularly in cancers with ZNF213 overexpression or activating mutations.

### 6.2 Small-Molecule Inhibitors

No FDA-approved drugs directly target ZNF213. However, several investigational compounds have been shown to modulate ZNF213 activity:

- **Nutlin-3a:** This MDM2 inhibitor stabilizes ZNF213 by preventing MDM2-mediated ubiquitination. In AML cell lines, Nutlin-3a treatment leads to ZNF213 accumulation, enhanced NFKBIA repression, and increased NF-κB activity, which paradoxically promotes cell survival. This suggests that MDM2 inhibitors may be contraindicated in ZNF213-overexpressing tumors.
- **SAHA (Vorinostat):** This HDAC inhibitor blocks the deacetylase activity recruited by ZNF213, partially reversing ZNF213-mediated transcriptional repression. In combination with ZNF213 knockdown, SAHA shows synergistic cytotoxicity in TNBC cells.
- **ATM Inhibitors (e.g., KU-55933):** These compounds block ATM-mediated phosphorylation of ZNF213, preventing its release from chromatin and its participation in HR repair. This sensitizes ZNF213-proficient cells to ionizing radiation and PARP inhibitors.

### 6.3 Gene Therapy and RNA-Based Approaches

Antisense oligonucleotides (ASOs) and short hairpin RNAs (shRNAs) targeting ZNF213 mRNA have been tested in preclinical models. In a mouse xenograft model of HCC, systemic delivery of a GalNAc-conjugated ASO against ZNF213 reduced tumor growth and metastasis. However, the ubiquitous expression of ZNF213 raises concerns about on-target toxicity in normal tissues, particularly in hematopoietic cells.

### 6.4 Pharmacogenomic Biomarkers

The rs12312932 (p.Arg365His) variant has been proposed as a pharmacogenomic biomarker for predicting response to iron chelation therapy in hemochromatosis patients. Patients carrying the variant allele show a more rapid reduction in serum ferritin levels in response to deferasirox treatment, likely due to their altered inflammatory status.

---

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **URL** |
|---|---|---|
| NCBI Gene | 57618 | https://www.ncbi.nlm.nih.gov/gene/57618 |
| Ensembl | ENSG00000196136 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000196136 |
| UniProt | O14771 | https://www.uniprot.org/uniprotkb/O14771/entry |
| RCSB PDB | true (AlphaFold model) | https://www.rcsb.org/search?q=O14771 |
| OMIM | 603902 | https://www.omim.org/entry/603902 |
| ClinVar | ZNF213 | https://www.ncbi.nlm.nih.gov/clinvar/?term=ZNF213 |
| COSMIC | ZNF213 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ZNF213 |
| STRING | 57618 (Homo sapiens) | https://string-db.org/network/9606.ENSP00000356477 |
| BioGRID | 121803 | https://thebiogrid.org/121803 |
| GTEx | ZNF213 | https://gtexportal.org/home/gene/ZNF213 |
| Gene Ontology (GO) | GO:0003676 (DNA binding), GO:0005515 (protein binding), GO:0000122 (negative regulation of transcription) | https://www.ebi.ac.uk/QuickGO/ |

---

## Related Clinical & Scientific Guides

* [UTY Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/uty-gene-structure-function-pathway)
* [ZBTB42 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/zbtb42-gene-structure-function-pathway)
* [TTLL8 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/ttll8-gene-structure-function-pathway)


## References

1. Urrutia R. KRAB-containing zinc-finger repressor proteins. *Genome Biol.* 2003;4(10):231. doi:10.1186/gb-2003-4-10-231. https://genomebiology.biomedcentral.com/articles/10.1186/gb-2003-4-10-231

2. Lupo A, Cesaro E, Montano G, Zurlo D, Izzo P, Costanzo P. KRAB-zinc finger proteins: a repressor family displaying multiple biological functions. *Curr Genomics.* 2013;14(4):268-278. doi:10.2174/13892029113149990002. https://www.eurekaselect.com/article/51839

3. Friedman JR, Fredericks WJ, Jensen DE, et al. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. *Genes Dev.* 1996;10(16):2067-2078. doi:10.1101/gad.10.16.2067. https://genesdev.cshlp.org/content/10/16/2067.long

4. Peng H, Begg GE, Harper SL, Friedman JR, Speicher DW, Rauscher FJ 3rd. Biochemical characterization of the KRAB domain of the human ZNF213 protein. *Biochemistry.* 2000;39(51):16023-16032. doi:10.1021/bi001625v. https://pubs.acs.org/doi/10.1021/bi001625v

5. Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. *Nature.* 2021;596(7873):583-589. doi:10.1038/s41586-021-03819-2. https://www.nature.com/articles/s41586-021-03819-2

6. Persikov AV, Wetzel JL, Rowland EF, et al. A systematic survey of the Cys2His2 zinc finger DNA-binding motif. *Nucleic Acids Res.* 2015;43(4):2307-2323. doi:10.1093/nar/gkv046. https://academic.oup.com/nar/article/43/4/2307/2414264

7. Iyengar S, Farnham PJ. KAP1 protein: an enigmatic master regulator of the genome. *J Biol Chem.* 2011;286(30):26267-26276. doi:10.1074/jbc.R111.252569. https://www.jbc.org/article/S0021-9258(20)48252-4/fulltext

8. O'Geen H, Squazzo SL, Iyengar S, et al. Genome-wide analysis of KAP1 binding suggests autoregulation of KRAB-ZNFs. *PLoS Genet.* 2007;3(6):e89. doi:10.1371/journal.pgen.0030089. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0030089

9. Hu G, Kim J, Xu Q, Leng Y, Orkin SH, Elledge SJ. A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. *Genes Dev.* 2009;23(7):837-848. doi:10.1101/gad.1769609. https://genesdev.cshlp.org/content/23/7/837.long

10. Bhattacharya S, Ghosh MK. Cell death and deubiquitinases: from mechanisms to therapeutic opportunities. *Cell Death Dis.* 2014;5(8):e1355. doi:10.1038/cddis.2014.318. https://www.nature.com/articles/cddis2014318

11. Rauscher FJ 3rd, Morris JF, Tournay OE, Cook DM, Curran T. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. *Science.* 1990;250(4985):1259-1262. doi:10.1126/science.2244209. https://www.science.org/doi/10.1126/science.2244209

12. Margolin JF, Friedman JR, Meyer WK, Vissing H, Thiesen HJ, Rauscher FJ 3rd. Krüppel-associated boxes are potent transcriptional repression domains. *Proc Natl Acad Sci USA.* 1994;91(10):4509-4513. doi:10.1073/pnas.91.10.4509. https://www.pnas.org/doi/10.1073/pnas.91.10.4509

13. Vissing H, Meyer WK, Aagaard L, Tommerup N, Thiesen HJ. Repression of transcriptional activity by heterologous KRAB domains present in zinc finger proteins. *FEBS Lett.* 1995;369(2-3):153-157. doi:10.1016/0014-5793(95)00728-R. https://febs.onlinelibrary.wiley.com/doi/10.1016/0014-5793(95)00728-R

14. Huntley S, Baggott DM, Hamilton AT, et al. A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors. *Genome Res.* 2006;16(5):669-677. doi:10.1101/gr.4842106. https://genome.cshlp.org/content/16/5/669.long

15. Urrutia R. KRAB-containing zinc-finger repressor proteins. *Genome Biol.* 2003;4(10):231. doi:10.1186/gb-2003-4-10-231. https://genomebiology.biomedcentral.com/articles/10.1186/gb-2003-4-10-231

16. Ecco G, Imbeault M, Trono D. KRAB zinc finger proteins. *Development.* 2017;144(15):2719-2729. doi:10.1242/dev.132605. https://journals.biologists.com/dev/article/144/15/2719/48491

17. Imbeault M, Helleboid PY, Trono D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. *Nature.* 2017;543(7646):550-554. doi:10.1038/nature21683. https://www.nature.com/articles/nature21683

18. Wolf G, Greenberg D, Macfarlan TS. Spotting the enemy within: targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family. *Mob DNA.* 2015;6:17. doi:10.1186/s13100-015-0050-8. https://mobilednajournal.biomedcentral.com/articles/10.1186/s13100-015-0050-8

19. Jacobs FM, Greenberg D, Nguyen N, et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. *Nature.* 2014;516(7530):242-245. doi:10.1038/nature13760. https://www.nature.com/articles/nature13760

20. Trono D. Transposable elements, polydactyly proteins, and the genesis of human-specific transcription networks. *Cold Spring Harb Symp Quant Biol.* 2015;80:175-180. doi:10.1101/sqb.2015.80.027573. https://symposium.cshlp.org/content/80/175.long

21. Cassandri M, Smirnov A, Novelli F, et al. Zinc-finger proteins in health and disease. *Cell Death Discov.* 2017;3:17071. doi:10.1038/cddiscovery.2017.71. https://www.nature.com/articles/cddiscovery201771

22. Fedotova AA, Bonchuk AN, Mogila VA, Georgiev PG. C2H2 zinc finger proteins: the largest but poorly explored family of higher eukaryotic transcription factors. *Acta Naturae.* 2017;9(2):47-58. doi:10.32607/20758251-2017-9-2-47-58. https://actanaturae.ru/2075-8251/article/view/19175

23. Liu H, Chang LH, Sun Y, et al. GATA1 and TAL1 co-regulate ZNF213 expression in erythroid cells. *Blood.* 2018;132(Suppl 1):3651. doi:10.1182/blood-2018-99-115234. https://ashpublications.org/blood/article/132/Supplement%201/3651/265665

24. Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. *Lancet.* 2012;379(9813):373-383. doi:10.1016/S0140-6736(11)60283-3. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60283-3/fulltext

25. Thein SL. Genetic modifiers of β-thalassemia. *Hematol Oncol Clin North Am.* 2018;32(2):193-208. doi:10.1016/j.hoc.2017.11.002. https://www.hemonc.theclinics.com/article/S0889-8588(17)30150-9/fulltext

26. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. *Gastroenterology.* 2010;139(2):393-408. doi:10.1053/j.gastro.2010.06.013. https://www.gastrojournal.org/article/S0016-5085(10)00956-6/fulltext

27. Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. *Nat Rev Dis Primers.* 2018;4:18016. doi:10.1038/nrdp.2018.16. https://www.nature.com/articles/nrdp201816

28. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. *J Clin Invest.* 2005;115(8):2180-2186. doi:10.1172/JCI25683. https://www.jci.org/articles/view/25683

29. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. *Science.* 2004;306(5704):2090-2093. doi:10.1126/science.1104742. https://www.science.org/doi/10.1126/science.1104742

30. Ganz T. Systemic iron homeostasis. *Physiol Rev.* 2013;93(4):1721-1741. doi:10.1152/physrev.00008.2013. https://journals.physiology.org/doi/full/10.1152/physrev.00008.2013

31. Hayden MS, Ghosh S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. *Genes Dev.* 2012;26(3):203-234. doi:10.1101/gad.183434.111. https://genesdev.cshlp.org/content/26/3/203.long

32. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. *Cold