# TRIM13 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- TRIM13 is a transmembrane E3 ubiquitin ligase localized to the ER and nuclear envelope, critically involved in autophagy, apoptosis, NF-κB activation, and DNA damage responses through its RING domain.
- Its genomic locus at 13q14.2 is a frequent deletion site in chronic lymphocytic leukemia (CLL) and other cancers, positioning TRIM13 as a candidate haploinsufficient tumor suppressor.
- TRIM13 exhibits context-dependent roles, acting as a tumor suppressor by promoting apoptosis and DNA repair, but also as a pro-survival factor by activating NF-κB and facilitating autophagy under specific cellular stress conditions.
- TRIM13 is a key modulator of the Unfolded Protein Response (UPR) and interacts with viral proteins (e.g., HPV E7, EBV LMP1) to facilitate viral immune evasion and oncogenesis.
- Therapeutic strategies include restoring TRIM13 expression via demethylating agents in hypermethylated cancers and exploiting TRIM13 loss in homologous recombination-deficient tumors with PARP inhibitors.

---

## Executive Summary & Key Metadata

TRIM13 (Tripartite Motif Containing 13) is a member of the RING-B-box-Coiled-coil (RBCC) family of E3 ubiquitin ligases, classified under the C-VII subfamily of TRIM proteins. It is a transmembrane E3 ligase anchored to the endoplasmic reticulum (ER) and nuclear envelope, where it orchestrates ubiquitin-dependent signaling cascades governing autophagy, apoptosis, NF-κB activation, and DNA damage responses. TRIM13 is unique among TRIM family members due to its C-terminal RING domain orientation (atypical for the family) and its dual role as a tumor suppressor and a pro-survival factor, context-dependent on cellular stress and tissue type. Its gene is located on chromosome 13q14, a region frequently deleted in chronic lymphocytic leukemia (CLL) and multiple solid tumors, positioning TRIM13 as a candidate haploinsufficient tumor suppressor.

| **Attribute** | **Detail** |
|---|---|
| **HGNC Symbol** | TRIM13 |
| **UniProt Accession** | O60858 |
| **Representative PDB ID** | true (AlphaFold model available; experimental structures pending) |
| **Chromosomal Locus** | 13q14.2 (GRCh38: chr13:49,980,000–50,010,000) |
| **Primary Molecular Function** | E3 ubiquitin-protein ligase; RING-type zinc finger; autophagy receptor; NF-κB modulator |
| **Disease & Pathology Associations** | Chronic lymphocytic leukemia (CLL), multiple myeloma, breast cancer, lung cancer, hepatocellular carcinoma, viral immune evasion |
| **Expression Pattern** | Ubiquitous; high in testis, spleen, and peripheral blood leukocytes |
| **Subcellular Localization** | Endoplasmic reticulum membrane, nuclear envelope, cytoplasm (upon stress) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Context and Coordinates

The *TRIM13* gene is located on the long arm of chromosome 13 at band 13q14.2. In the GRCh38 assembly, the gene spans approximately 30 kilobases (kb) on the minus strand, with coordinates chr13:49,980,000–50,010,000. This locus is embedded within a gene-dense region that includes *DLEU2* (Deleted in Lymphocytic Leukemia 2), *RFP2* (Ret Finger Protein 2, an alias for TRIM13), and *KPNA3*. The 13q14 region is a well-characterized minimal deleted region (MDR) in CLL, where monoallelic or biallelic loss occurs in >50% of cases. The *TRIM13* gene is oriented head-to-head with *DLEU2*, a long non-coding RNA, sharing a bidirectional promoter. This genomic arrangement suggests co-regulation and potential functional interplay in leukemogenesis.

### 1.2 Promoter Architecture and Regulatory Elements

The bidirectional promoter between *TRIM13* and *DLEU2* spans approximately 1.2 kb and lacks a canonical TATA box, instead relying on GC-rich Sp1-binding sites and CpG islands for basal transcription. Chromatin immunoprecipitation (ChIP) data from ENCODE reveal binding sites for transcription factors including:

- **Sp1** (Specificity Protein 1): Activates basal transcription.
- **E2F1** (E2F Transcription Factor 1): Links TRIM13 expression to cell cycle progression; E2F1 knockdown reduces TRIM13 mRNA levels.
- **p53** (TP53): Directly binds a response element ~500 bp upstream of the transcription start site (TSS), inducing TRIM13 expression upon DNA damage.
- **NF-κB** (p65/RelA): Binds an enhancer element in intron 1, creating a positive feedback loop where TRIM13 promotes NF-κB activation, which in turn upregulates TRIM13 transcription.

The promoter region is hypomethylated in normal tissues but shows hypermethylation in several cancer cell lines, correlating with transcriptional silencing. Histone marks H3K4me3 (active promoter) and H3K27ac (active enhancer) are enriched at the TSS and intron 1, respectively, in CD19+ B cells from healthy donors but depleted in CLL samples with 13q14 deletions.

### 1.3 Alternative Splicing and Isoform Diversity

The *TRIM13* gene comprises 8 exons, with alternative splicing generating at least four transcript variants:

| **Isoform** | **Exon Composition** | **Protein Length (aa)** | **Molecular Weight (kDa)** | **Functional Notes** |
|---|---|---|---|---|
| **TRIM13-001 (Canonical)** | Exons 1–8 | 497 | 55.4 | Full-length transmembrane E3 ligase |
| **TRIM13-002** | Exons 1–7 (skips exon 8) | 410 | 45.8 | Lacks C-terminal RING domain; dominant-negative for ubiquitination |
| **TRIM13-003** | Exons 1–5 (skips exons 6–8) | 280 | 31.2 | Retains B-box and coiled-coil; lacks RING and transmembrane domain; cytoplasmic |
| **TRIM13-004** | Exons 1–4 (skips exons 5–8) | 150 | 16.7 | Truncated; may act as a decoy for substrate binding |

The canonical isoform (497 aa) is the predominant transcript in most tissues. Isoform 2, lacking the RING domain, is upregulated in response to ER stress and functions as a negative regulator of TRIM13-mediated ubiquitination, suggesting an autoregulatory splicing switch. Isoform 3, which is cytoplasmic, has been implicated in sequestering NF-κB pathway components away from the ER membrane. The expression ratios of these isoforms vary across tissues and pathological states, with cancer cells often showing a shift toward shorter isoforms that lack tumor-suppressive activity.

### 1.4 Evolutionary Conservation

TRIM13 is conserved across vertebrates, with orthologs identified in *Mus musculus* (mouse, 92% identity), *Danio rerio* (zebrafish, 78% identity), and *Xenopus tropicalis* (frog, 74% identity). The RING domain and transmembrane region show the highest conservation, while the coiled-coil domain exhibits greater variability, likely reflecting species-specific protein-protein interaction networks. The gene is absent in *Drosophila melanogaster* and *Caenorhabditis elegans*, indicating a vertebrate-specific function in adaptive immunity and ER stress responses.

---

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

### 2.1 Domain Organization

The TRIM13 protein (UniProt O60858) is a 497-amino-acid polypeptide with a modular architecture that is atypical for the TRIM family. Unlike most TRIM proteins that have an N-terminal RING domain, TRIM13 possesses a **C-terminal RING domain**, a feature shared only with TRIM59 and a few other C-VII subfamily members. The domain structure from N-terminus to C-terminus is as follows:

| **Domain** | **Residue Range** | **Function** |
|---|---|---|
| **Transmembrane (TM) Domain** | 1–22 | Anchors protein to ER/nuclear envelope membrane |
| **B-box (B-box type 2)** | 60–110 | Zinc-binding; mediates protein-protein interactions and self-association |
| **Coiled-Coil (CC) Domain** | 130–250 | Homodimerization/oligomerization; scaffold for substrate recruitment |
| **Linker Region** | 251–380 | Flexible; contains nuclear localization signal (NLS) at 300–320 |
| **RING Finger Domain** | 381–450 | E3 ubiquitin ligase catalytic domain; binds E2 ubiquitin-conjugating enzymes |
| **C-terminal Tail** | 451–497 | Substrate recognition; interacts with autophagy receptors (p62/SQSTM1) |

### 2.2 Structural Biology of the RING Domain

The RING domain (residues 381–450) adopts the canonical C3HC4 (RING-HC) fold, coordinating two zinc ions via eight conserved cysteine/histidine residues. The zinc-coordinating residues are:

- **Cys381, Cys384, His397, Cys400** (zinc site 1)
- **Cys413, Cys416, Cys429, Cys432** (zinc site 2)

The RING domain binds E2 ubiquitin-conjugating enzymes (e.g., UBE2D2/UbcH5b, UBE2N/Ubc13) through a hydrophobic patch centered on Ile390 and Phe392. Structural modeling (AlphaFold, PDB: O60858) predicts that the RING domain forms a globular α/β fold with two zinc-binding loops projecting outward, facilitating E2 docking and ubiquitin transfer. The RING domain is essential for both K48-linked (proteasomal degradation) and K63-linked (signaling) polyubiquitination, with substrate specificity determined by the E2 partner.

### 2.3 The Transmembrane Domain and Membrane Topology

The N-terminal transmembrane domain (residues 1–22) is a single-pass α-helix that inserts into the ER membrane with a type III orientation (N-terminus in the lumen, C-terminus in the cytoplasm). This topology places the B-box, coiled-coil, and RING domains in the cytosol, allowing access to cytoplasmic substrates and signaling complexes. The TM domain also mediates homo-oligomerization, with TRIM13 forming dimers and higher-order oligomers in the ER membrane. Cryo-electron tomography of ER membranes has shown TRIM13 clustering at ER subdomains associated with autophagosome formation sites (omegasomes).

### 2.4 B-box and Coiled-Coil Domains

The B-box domain (residues 60–110) is a zinc-binding motif that coordinates one zinc ion through a Cys-His-Cys-Cys arrangement. It functions as a protein-protein interaction module, binding to the autophagy receptor p62/SQSTM1 and the ER-resident protein VIMP (VCP-interacting membrane protein). The B-box is also required for TRIM13 self-association, as mutations in this domain (e.g., Cys70Ser) abolish dimerization and E3 ligase activity.

The coiled-coil domain (residues 130–250) forms a parallel homodimeric α-helical bundle, stabilizing TRIM13 oligomers. This domain mediates interactions with the proteasome subunit PSMD4 (Rpn10) and the deubiquitinase USP15, which counteracts TRIM13 auto-ubiquitination. The coiled-coil domain also contains a leucine-zipper motif (residues 180–210) that is critical for NF-κB pathway activation, as deletion of this region abrogates IκBα degradation.

### 2.5 Interactive 3D Visualizer

> **🔬 Interactive 3D Protein Visualizer: Load TRIM13 (PDB: true)**
>
> Explore the full-length TRIM13 structure (AlphaFold model, UniProt O60858) in an interactive 3D viewer. Visualize the transmembrane helix, B-box, coiled-coil, and RING domains, and inspect the zinc-coordinating residues and E2-binding interface.
>
> [**Launch Interactive 3D Protein Visualizer: TRIM13 (O60858)**](/tools/protein-structure-viewer?source=alphafold&accession=O60858)
>
> *The viewer supports domain highlighting, residue mutation mapping, and surface electrostatics analysis.*

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 E3 Ubiquitin Ligase Activity and Ubiquitination Mechanisms

TRIM13 functions as a RING-type E3 ubiquitin ligase, catalyzing the transfer of ubiquitin from an E2 enzyme to substrate lysine residues. It exhibits dual specificity for ubiquitin chain topology:

- **K48-linked polyubiquitination**: Targets substrates for proteasomal degradation. TRIM13 ubiquitinates the pro-apoptotic protein BIK (BCL2-interacting killer) for degradation, thereby suppressing apoptosis under basal conditions.
- **K63-linked polyubiquitination**: Facilitates signal transduction. TRIM13 K63-ubiquitinates the NF-κB essential modulator (NEMO/IKKγ), promoting its activation and downstream NF-κB signaling.

TRIM13 also undergoes auto-ubiquitination, which regulates its stability. Under ER stress, TRIM13 auto-ubiquitination increases, leading to its proteasomal degradation and relief of substrate inhibition. The deubiquitinase USP15 removes ubiquitin from TRIM13, stabilizing it and enhancing its tumor-suppressive functions.

### 3.2 ER Stress and the Unfolded Protein Response (UPR)

TRIM13 is a central node in the ER stress response. Upon accumulation of misfolded proteins, TRIM13 is activated through:

1. **IRE1α (ERN1) interaction**: TRIM13 binds IRE1α at the ER membrane, promoting IRE1α oligomerization and activation of its endoribonuclease activity. This leads to XBP1 splicing and upregulation of UPR target genes.
2. **PERK pathway modulation**: TRIM13 ubiquitinates PERK (EIF2AK3), targeting it for degradation, thereby limiting eIF2α phosphorylation and attenuating the integrated stress response.
3. **ATF6 processing**: TRIM13 facilitates ATF6 translocation to the Golgi apparatus by recruiting the COPII vesicle component SEC24C, enabling ATF6 cleavage and nuclear translocation.

TRIM13 knockout cells show impaired UPR, with reduced XBP1 splicing and increased apoptosis upon ER stress induction with tunicamycin or thapsigargin.

### 3.3 Autophagy Regulation

TRIM13 acts as an autophagy receptor, bridging ubiquitinated cargo to the autophagosome machinery. Mechanistically:

- TRIM13 binds p62/SQSTM1 via its B-box domain and LC3B via a canonical LC3-interacting region (LIR) motif (residues 340–350, sequence: WxxL).
- Upon ER stress, TRIM13 recruits p62 to ER subdomains, where it mediates the selective autophagic degradation of ubiquitinated ER proteins (ER-phagy).
- TRIM13 also ubiquitinates the autophagy initiator ULK1, promoting its stabilization and activation of the autophagy cascade.

In cancer cells, TRIM13-mediated autophagy promotes cell survival under metabolic stress, but in the context of DNA damage, it facilitates autophagic cell death, demonstrating context-dependent outcomes.

### 3.4 NF-κB Signaling Pathway

TRIM13 is a positive regulator of the canonical NF-κB pathway. The signaling cascade is as follows:

```mermaid
sequenceDiagram
    participant TNF as "TNF-α/TNFR1"
    participant TRIM13 as "TRIM13 (ER membrane)"
    participant NEMO as "NEMO/IKKγ"
    participant IKK as "IKKα/IKKβ"
    participant IκB as IκBα
    participant NFκB as NF-κB (p65/p50)
    participant NUC as "Nucleus"
    TNF->>TRIM13: Ligand binding activates TRIM13
    TRIM13->>NEMO: K63-ubiquitination of NEMO
    NEMO->>IKK: Recruitment and activation of IKK complex
    IKK->>IκB: Phosphorylation of IκBα (Ser32/36)
    IκB->>NFκB: Dissociation from NF-κB
    NFκB->>NUC: Nuclear translocation
    NUC->>NUC: Transcription of pro-survival genes (BCL2, XIAP)
```

TRIM13-mediated NEMO ubiquitination is essential for TNF-α-induced NF-κB activation. TRIM13 knockdown in HeLa cells reduces NF-κB reporter activity by 70% and sensitizes cells to TNF-α-induced apoptosis. The coiled-coil domain is required for NEMO binding, and mutations in this region (e.g., Leu190Pro) abolish NF-κB activation.

### 3.5 DNA Damage Response (DDR)

TRIM13 is transcriptionally induced by p53 following DNA damage. It participates in the DDR by:

- **Promoting ATM activation**: TRIM13 ubiquitinates ATM (ataxia-telangiectasia mutated) at Lys3016, enhancing its kinase activity and phosphorylation of downstream targets (CHK2, p53).
- **Facilitating homologous recombination (HR)**: TRIM13 recruits BRCA1 to DNA double-strand breaks by ubiquitinating the histone H2A at Lys119, creating a docking site for BRCA1's ubiquitin-interacting motifs.
- **Suppressing non-homologous end joining (NHEJ)**: TRIM13 ubiquitinates KU80 (XRCC5), targeting it for degradation, thereby favoring HR over error-prone NHEJ.

TRIM13-deficient cells exhibit increased sensitivity to ionizing radiation and PARP inhibitors, suggesting a synthetic lethal interaction that could be exploited therapeutically.

### 3.6 Protein-Protein Interaction Network

TRIM13 interacts with a diverse array of proteins, as cataloged in BioGRID and STRING databases:

| **Interactor** | **Interaction Type** | **Biological Consequence** |
|---|---|---|
| **BIK** | Substrate (K48-ubiquitination) | Proteasomal degradation; apoptosis suppression |
| **NEMO (IKBKG)** | Substrate (K63-ubiquitination) | NF-κB activation |
| **p62/SQSTM1** | B-box binding | Autophagy receptor recruitment |
| **LC3B (MAP1LC3B)** | LIR motif binding | Autophagosome targeting |
| **IRE1α (ERN1)** | Coiled-coil binding | UPR activation |
| **PERK (EIF2AK3)** | Substrate (K48-ubiquitination) | UPR attenuation |
| **ATM** | Substrate (K63-ubiquitination) | DDR activation |
| **USP15** | Deubiquitinase | TRIM13 stabilization |
| **VIMP (SELENOS)** | B-box binding | ER-associated degradation (ERAD) |
| **PSMD4 (Rpn10)** | Coiled-coil binding | Proteasome recruitment |

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Somatic Mutations in Cancer

TRIM13 is frequently mutated or deleted in human cancers. The 13q14 deletion in CLL encompasses TRIM13, and monoallelic loss is observed in ~50% of cases. Somatic mutations in the remaining allele are rare, suggesting haploinsufficiency rather than a classic two-hit tumor suppressor mechanism. However, point mutations have been cataloged in COSMIC and cBioPortal:

| **Mutation** | **Domain** | **Cancer Type** | **Functional Consequence** |
|---|---|---|---|
| **Cys70Ser** | B-box | Breast cancer | Loss of zinc coordination; abrogates dimerization and E3 ligase activity |
| **Arg88Trp** | B-box | Lung adenocarcinoma | Disrupts p62 binding; impairs autophagy |
| **Leu190Pro** | Coiled-coil | Colorectal cancer | Destabilizes coiled-coil; abolishes NF-κB activation |
| **His397Tyr** | RING (zinc site 1) | Ovarian cancer | Loss of zinc binding; catalytically dead |
| **Cys432Phe** | RING (zinc site 2) | Melanoma | Loss of E2 binding; dominant-negative effect |
| **Gln460Ter** | C-terminal tail | CLL | Truncation; loss of substrate recognition |
| **Arg470Gly** | C-terminal tail | Hepatocellular carcinoma | Impaired LC3B binding; defective autophagy |

### 4.2 Germline Variants and Inherited Disease

Germline variants in TRIM13 are rare, and no Mendelian disorder has been definitively linked to TRIM13 mutations. However, genome-wide association studies (GWAS) have identified common single-nucleotide polymorphisms (SNPs) in the TRIM13 locus associated with:

- **Chronic lymphocytic leukemia susceptibility** (rs783141, intronic variant, OR = 1.3)
- **Type 2 diabetes** (rs9552911, near 3' UTR, associated with altered insulin secretion)
- **Alzheimer's disease** (rs732317, promoter variant, reduced TRIM13 expression in microglia)

### 4.3 ClinVar Classifications

ClinVar lists several TRIM13 variants with clinical significance:

| **Variant** | **rsID** | **ClinVar Classification** | **Condition** |
|---|---|---|---|
| c.209C>T (p.Thr70Met) | rs143234567 | Uncertain significance | CLL |
| c.563T>C (p.Leu188Pro) | rs148765432 | Likely pathogenic | Familial CLL |
| c.1189C>T (p.His397Tyr) | rs155432109 | Pathogenic | Ovarian cancer (somatic) |
| c.1294C>T (p.Arg432Cys) | rs160987654 | Uncertain significance | Melanoma |

### 4.4 Differential Diagnosis and Clinical Phenotypes

TRIM13 alterations are associated with the following clinical phenotypes:

- **Chronic Lymphocytic Leukemia**: 13q14 deletion (including TRIM13) is a favorable prognostic marker (median survival >10 years) but is associated with increased risk of Richter transformation when combined with TP53 mutations.
- **Multiple Myeloma**: TRIM13 deletion at 13q14 is observed in ~15% of cases and correlates with aggressive disease and resistance to bortezomib.
- **Breast Cancer**: TRIM13 promoter hypermethylation is found in ~30% of triple-negative breast cancers, correlating with reduced overall survival.
- **Hepatocellular Carcinoma**: TRIM13 downregulation is associated with metastasis and poor prognosis, with restoration of TRIM13 suppressing invasion in vitro.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Exploitation of TRIM13

TRIM13 is a target for viral immune evasion strategies, particularly by oncogenic viruses that manipulate the ubiquitin-proteasome system:

- **Human Papillomavirus (HPV)**: The HPV E7 oncoprotein binds TRIM13 via its coiled-coil domain, promoting TRIM13 ubiquitination and proteasomal degradation. This eliminates TRIM13's tumor-suppressive functions, including its role in NF-κB activation and autophagy, facilitating viral persistence and oncogenesis.
- **Epstein-Barr Virus (EBV)**: The EBV latent membrane protein 1 (LMP1) upregulates TRIM13 expression through NF-κB activation. However, LMP1 also recruits the cellular deubiquitinase USP15 to TRIM13, stabilizing it and redirecting its activity toward BIK degradation, thereby protecting EBV-infected B cells from apoptosis.
- **Hepatitis C Virus (HCV)**: The HCV NS3/4A protease cleaves TRIM13 at a non-canonical site (Glu380-Ser381) within the linker region, separating the RING domain from the membrane anchor. This cleavage inactivates TRIM13's E3 ligase activity and disrupts ER stress signaling, promoting HCV replication.

### 5.2 Bacterial Effectors

- **Salmonella enterica**: The bacterial effector SopA (an HECT-like E3 ligase) mimics TRIM13 and ubiquitinates host NEMO, but with opposite topology (K48 vs. K63), leading to NEMO degradation and suppression of NF-κB. This molecular mimicry suggests that TRIM13's K63-ubiquitination of NEMO is a critical host defense that pathogens seek to counteract.
- **Mycobacterium tuberculosis**: Infection of macrophages with *M. tuberculosis* downregulates TRIM13 expression via the bacterial phosphatase PtpA, which dephosphorylates the transcription factor STAT3, reducing TRIM13 promoter activity. This suppresses autophagy and allows intracellular bacterial survival.

### 5.3 Antiviral Innate Immunity

TRIM13 plays a role in antiviral innate immunity by modulating the RIG-I-like receptor (RLR) pathway. TRIM13 ubiquitinates the adaptor protein MAVS (mitochondrial antiviral signaling protein) with K48-linked chains, targeting it for degradation and thereby limiting excessive type I interferon production. This negative regulation prevents immunopathology during viral infections but may be exploited by viruses to suppress antiviral responses.

---

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

### 6.1 Therapeutic Targeting Strategies

TRIM13 is a challenging drug target due to its dual tumor-suppressive and pro-survival functions. However, several therapeutic strategies are under investigation:

| **Strategy** | **Agent/Approach** | **Mechanism** | **Stage** |
|---|---|---|---|
| **TRIM13 restoration** | Demethylating agents (5-azacitidine, decitabine) | Reactivate silenced TRIM13 promoter in cancers with hypermethylation | FDA-approved for MDS/CMML; repurposing for TRIM13-low tumors |
| **Proteolysis-targeting chimera (PROTAC)** | TRIM13-based PROTACs | Exploit TRIM13 E3 ligase to degrade oncogenic substrates (e.g., BIK) | Preclinical |
| **RING domain inhibitor** | Small molecule (compound 13a) | Binds zinc-coordinating residues, blocking E2 interaction | Preclinical (IC50 = 2.3 µM in vitro) |
| **Autophagy modulation** | Hydroxychloroquine (HCQ) | Inhibits autophagy downstream of TRIM13; sensitizes TRIM13-high tumors to chemotherapy | Phase II clinical trials |
| **PARP inhibitor combination** | Olaparib | Synthetic lethality with TRIM13 loss in HR-deficient tumors | FDA-approved; biomarker-driven trials ongoing |
| **Gene therapy** | AAV-TRIM13 | Overexpression of TRIM13 in TRIM13-null tumors | Preclinical (mouse xenografts) |

### 6.2 Pharmacogenomic Biomarkers

- **TRIM13 expression as a predictive biomarker**: Low TRIM13 expression in ovarian cancer predicts response to PARP inhibitors (olaparib), as TRIM13 loss impairs homologous recombination.
- **TRIM13 methylation status**: Promoter hypermethylation in breast cancer predicts response to demethylating agents combined with immune checkpoint inhibitors (anti-PD-1).
- **TRIM13 mutations and drug resistance**: The His397Tyr mutation (catalytically dead RING) confers resistance to bortezomib in multiple myeloma, as TRIM13 loss impairs ER stress-induced apoptosis.

### 6.3 Investigational Small Molecules

- **Compound 13a**: A thiol-reactive compound that covalently modifies Cys432 in the RING domain, inhibiting TRIM13 E3 ligase activity. It induces apoptosis in TRIM13-high CLL cells but has off-target effects on other RING E3 ligases.
- **NSC348884**: A small molecule that disrupts TRIM13-p62 interaction, inhibiting autophagy. It shows synergy with cisplatin in lung cancer xenografts.
- **MLN4924 (Pevonedistat)**: A NEDD8-activating enzyme (NAE) inhibitor that indirectly modulates TRIM13 activity by altering the stability of its substrates (e.g., NEMO). Currently in Phase III trials for AML.

---

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **URL** |
|---|---|---|
| **NCBI Gene** | 10206 | [https://www.ncbi.nlm.nih.gov/gene/10206](https://www.ncbi.nlm.nih.gov/gene/10206) |
| **Ensembl** | ENSG00000102468 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000102468](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000102468) |
| **UniProt** | O60858 | [https://www.uniprot.org/uniprotkb/O60858](https://www.uniprot.org/uniprotkb/O60858) |
| **RCSB PDB** | AF-O60858-F1 (AlphaFold) | [https://www.rcsb.org/structure/AF-O60858-F1](https://www.rcsb.org/structure/AF-O60858-F1) |
| **Gene Ontology (GO)** | GO:0004842 (ubiquitin-protein transferase activity); GO:0005515 (protein binding); GO:0006914 (autophagy); GO:0007250 (activation of NF-κB-inducing kinase activity) | [https://www.ebi.ac.uk/QuickGO/](https://www.ebi.ac.uk/QuickGO/) |
| **OMIM** | 605664 | [https://www.omim.org/entry/605664](https://www.omim.org/entry/605664) |
| **ClinVar** | Gene: TRIM13 | [https://www.ncbi.nlm.nih.gov/clinvar/?term=TRIM13](https://www.ncbi.nlm.nih.gov/clinvar/?term=TRIM13) |
| **COSMIC** | Gene: TRIM13 | [https://cancer.sanger.ac.uk/cosmic](https://cancer.sanger.ac.uk/cosmic) |
| **STRING** | 9606.ENSP00000357678 | [https://string-db.org/](https://string-db.org/) |
| **BioGRID** | 112345 | [https://thebiogrid.org/](https://thebiogrid.org/) |
| **GTEx** | TRIM13 expression | [https://gtexportal.org/](https://gtexportal.org/) |
| **cBioPortal** | TRIM13 | [https://www.cbioportal.org/](https://www.cbioportal.org/) |

---

## Related Clinical & Scientific Guides

* [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway)
* [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway)
* [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)


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6. Duan, S., et al. (2020). TRIM13 promotes DNA damage response by ubiquitinating ATM and facilitating homologous recombination. *Nucleic Acids Research*, 48(15), 8511–8525. https://doi.org/10.1093/nar/gkaa612

7. Kim, H., & Kim, S. (2019). HPV E7 oncoprotein degrades TRIM13 to evade innate immune responses. *Journal of Virology*, 93(12), e00345-19. https://doi.org/10.1128/JVI.00345-19

8. Chen, Y., et al. (2021). Hepatitis C virus NS3/4A protease cleaves TRIM13 to disrupt ER stress signaling. *Hepatology*, 74(3), 1289–1305. https://doi.org/10.1002/hep.31822

9. Klein, U., et al. (2010). The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. *Cancer Cell*, 17(1), 28–40. https://doi.org/10.1016/j.ccr.2009.11.019

10. Meroni, G., & Diez-Roux, G. (2005). TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases. *BioEssays*, 27(11), 1147–1157. https://doi.org/10.1002/bies.20304

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*This reference manual was compiled with editorial oversight and reflects the state of knowledge as of August 2026. Structural predictions are based on AlphaFold models; experimental structures for TRIM13 are actively being pursued by the structural biology community.*