Details for: GEN1

Gene ID: 348654

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GEN1

Ensembl ID: ENSG00000178295

Description: GEN1 Holliday junction 5' flap endonuclease

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • retinal pigment epithelial cell CL0002586
    CSI 10.03
    rCSI 19.92%
    PRS 95.11
  • choroid plexus epithelial cell CL0000706
    CSI 4.97
    rCSI 8.13%
    PRS 93.93
  • melanocyte CL0000148
    CSI 4.2
    rCSI 3.11%
    PRS 95.31
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 3.3
    rCSI 3.81%
    PRS 92.85
  • colon epithelial cell CL0011108
    CSI 3.14
    rCSI 3.29%
    PRS 95.79
  • hepatic stellate cell CL0000632
    CSI 2.98
    rCSI 11.15%
    PRS 95.52
  • cerebral cortex endothelial cell CL1001602
    CSI 2.97
    rCSI 5.13%
    PRS 94.81
  • Kupffer cell CL0000091
    CSI 2.88
    rCSI 6.58%
    PRS 97.39
  • cardiac endothelial cell CL0010008
    CSI 2.64
    rCSI 10.65%
    PRS 97.24
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.61
    rCSI 3.24%
    PRS 89.74
  • conjunctival epithelial cell CL1000432
    CSI 2.39
    rCSI 3.65%
    PRS 96.17
  • extravillous trophoblast CL0008036
    CSI 2.3
    rCSI 2.84%
    PRS 95.86
  • erythroblast CL0000765
    CSI 1.53
    rCSI 4.07%
    PRS 96.68
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.95
    rCSI 2.98%
    PRS 91.82
  • enterocyte of epithelium of large intestine CL0002071
    CSI 0.91
    rCSI 4.78%
    PRS 97.38
  • blood vessel smooth muscle cell CL0019018
    CSI 0.54
    rCSI 4.36%
    PRS 96.47
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.49
    rCSI 11.87%
    PRS 88.78

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [GEN1](/details-gene/348654) (GEN1 Holliday junction 5' flap endonuclease) is a protein-coding gene located on chromosome 2p24.2. It encodes a crucial DNA repair enzyme that functions as a Holliday junction resolvase. Its primary role involves the processing and resolution of DNA recombination intermediates, a critical step in maintaining genomic stability during double-strand break repair via homologous recombination. Consistent with this fundamental role, functional annotations place it squarely within pathways of [Dna repair](/details-pathway/R-HSA-73894) and the cell cycle. Expression data from the **Overall** context indicates that [GEN1](/details-gene/348654) has its highest significance in [retinal pigment epithelial cell](/details-cell/CL0002586), suggesting a specialized requirement for its activity in this cell type, likely to counteract high levels of oxidative and phototoxic stress. ## Cellular Roles and Expression Landscape The expression profile of [GEN1](/details-gene/348654) highlights its importance in a diverse set of cell types that are either highly metabolically active, exposed to environmental stressors, or possess proliferative potential. **Overall**, the gene's most significant expression is observed in [retinal pigment epithelial cell](/details-cell/CL0002586) (CSI: 10.03), a cell type responsible for maintaining photoreceptor health and known to experience significant oxidative stress. High significance is also noted in other specialized epithelial cells, including [choroid plexus epithelial cell](/details-cell/CL0000706) and [conjunctival epithelial cell](/details-cell/CL1000432), as well as in pigment-producing [melanocyte](/details-cell/CL0000148). Its presence in progenitor populations such as [neuroblast (sensu Nematoda and Protostomia)](/details-cell/CL0000338) and [erythroblast](/details-cell/CL0000765) is consistent with its role in safeguarding genomic integrity during cell division and differentiation. The gene's activity in various endothelial cells, such as [cerebral cortex endothelial cell](/details-cell/CL1001602) and [cardiac endothelial cell](/details-cell/CL0010008), further suggests a broad role in maintaining cellular health across different tissues. ## Pathways and Molecular Function [GEN1](/details-gene/348654) is a highly specialized endonuclease central to the final stages of homologous recombination. Its function was established in a landmark study identifying it as a human Holliday junction resolvase ([Link](https://doi.org/10.1038/nature07470)). **Biological Process:** The gene is annotated with processes critical for DNA metabolism, including [Double-strand break repair via homologous recombination](/details-ontology/GO:0000724), [Replication fork processing](/details-ontology/GO:0031297), and specifically, the [Resolution of dna recombination intermediates](/details-ontology/GO:0071139). This function is supported by Reactome pathways such as [Resolution of d-loop structures through holliday junction intermediates](/details-pathway/R-HSA-5693568) and [Homology directed repair (hdr)](/details-pathway/R-HSA-5693538). Its involvement in cell cycle regulation is suggested by annotations for [Positive regulation of mitotic cell cycle spindle assembly checkpoint](/details-ontology/GO:0090267) and its localization to the [Centrosome](/details-ontology/GO:0005813). **Molecular Function:** At the molecular level, [GEN1](/details-gene/348654) exhibits [5'-flap endonuclease activity](/details-ontology/GO:0017108) and [Crossover junction dna endonuclease activity](/details-ontology/GO:0008821). It recognizes and binds to its substrate via [Four-way junction dna binding](/details-ontology/GO:0000400) activity, a process facilitated by a chromodomain ([Link](https://doi.org/10.7554/elife.12256)). Mechanistic studies have shown that it resolves Holliday junctions through a coordinated nick and counter-nick mechanism ([Link](https://doi.org/10.1093/nar/gkv1207), [Link](https://doi.org/10.1073/pnas.1619790114)), ensuring the proper segregation of chromosomes during mitosis. ## Research Directions The specific expression patterns and fundamental role of [GEN1](/details-gene/348654) in DNA repair suggest several avenues for future research, particularly concerning its role in tissue-specific pathologies and as a potential therapeutic target. **Proposed Hypotheses:** 1. Given its exceptionally high significance in [retinal pigment epithelial cell](/details-cell/CL0002586), we hypothesize that **[GEN1](/details-gene/348654) is a critical factor in mitigating DNA damage induced by photo-oxidative stress in the retina, and that reduced [GEN1](/details-gene/348654) function could be a contributing factor to the pathogenesis of age-related macular degeneration (AMD) or other retinal degenerative diseases.** 2. Based on its function in resolving mitotic recombination intermediates and its expression in progenitor cells, we hypothesize that **deficiency in [GEN1](/details-gene/348654) leads to increased genomic instability in rapidly proliferating cells, potentially contributing to developmental defects or providing a permissive environment for oncogenic transformation.** **Experimental Approach:** To test the first hypothesis, one could utilize an in vitro model system. The [GEN1](/details-gene/348654) gene could be knocked out in a human retinal pigment epithelial cell line (e.g., ARPE-19) using CRISPR-Cas9. These knockout cells, along with wild-type controls, would then be exposed to a source of photo-oxidative stress, such as high-intensity blue light or hydrogen peroxide. The cellular response could be quantified by measuring levels of DNA double-strand breaks (via γH2AX foci staining), assessing cell cycle progression through flow cytometry, and monitoring rates of apoptosis (e.g., using Annexin V staining). A significant increase in DNA damage and cell death in the [GEN1](/details-gene/348654)-knockout cells would support its protective role in the RPE. **Therapeutic Potential:** As a key enzyme in the homologous recombination pathway, [GEN1](/details-gene/348654) represents a potential therapeutic target in oncology. Many cancer cells, particularly those with defects in other DNA repair pathways (e.g., BRCA1/2 mutations), become highly dependent on remaining repair mechanisms for survival. Therefore, **inhibition** of [GEN1](/details-gene/348654) could induce synthetic lethality in such tumors. A small molecule inhibitor of [GEN1](/details-gene/348654) could be used as a monotherapy in cancers with specific genetic vulnerabilities or in combination with DNA-damaging agents (chemotherapy, radiation) or PARP inhibitors to potentiate their effects. This strategy would be particularly relevant for cancers where DNA repair pathways are known to be dysregulated, such as in certain breast, colorectal, or renal cancers ([Link](https://doi.org/10.1126/science.1133427), [Link](https://doi.org/10.1038/nature09639)).

Genular Protein ID: 1826513928

Symbol: GEN_HUMAN

Name: Flap endonuclease GEN homolog 1

UniProtKB Accession Codes:

Q17RS7 Q17RS9 Q6ZN37

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 8 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 4 Ensembl 2 ExpressionAtlas 1 GO 13 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 7 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 7 SIGNOR 1 SMART 3 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 19020614

Title: Identification of Holliday junction resolvases from humans and yeast.

PubMed ID: 19020614

DOI: 10.1038/nature07470

PubMed ID: 26578604

Title: GEN1 promotes Holliday junction resolution by a coordinated nick and counter-nick mechanism.

PubMed ID: 26578604

DOI: 10.1093/nar/gkv1207

PubMed ID: 28049850

Title: Resolution of single and double Holliday junction recombination intermediates by GEN1.

PubMed ID: 28049850

DOI: 10.1073/pnas.1619790114

PubMed ID: 26682650

Title: Human Holliday junction resolvase GEN1 uses a chromodomain for efficient DNA recognition and cleavage.

PubMed ID: 26682650

DOI: 10.7554/elife.12256

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 21248752

Title: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.

PubMed ID: 21248752

DOI: 10.1038/nature09639

Sequence Information:

  • Length: 908
  • Mass: 102884
  • Checksum: 3C9DB87DDBD0C58F
  • Sequence:
    • MGVNDLWQIL EPVKQHIPLR NLGGKTIAVD LSLWVCEAQT VKKMMGSVMK PHLRNLFFRI 
SYLTQMDVKL VFVMEGEPPK LKADVISKRN QSRYGSSGKS WSQKTGRSHF KSVLRECLHM 
LECLGIPWVQ AAGEAEAMCA YLNAGGHVDG CLTNDGDTFL YGAQTVYRNF TMNTKDPHVD 
CYTMSSIKSK LGLDRDALVG LAILLGCDYL PKGVPGVGKE QALKLIQILK GQSLLQRFNR 
WNETSCNSSP QLLVTKKLAH CSVCSHPGSP KDHERNGCRL CKSDKYCEPH DYEYCCPCEW 
HRTEHDRQLS EVENNIKKKA CCCEGFPFHE VIQEFLLNKD KLVKVIRYQR PDLLLFQRFT 
LEKMEWPNHY ACEKLLVLLT HYDMIERKLG SRNSNQLQPI RIVKTRIRNG VHCFEIEWEK 
PEHYAMEDKQ HGEFALLTIE EESLFEAAYP EIVAVYQKQK LEIKGKKQKR IKPKENNLPE 
PDEVMSFQSH MTLKPTCEIF HKQNSKLNSG ISPDPTLPQE SISASLNSLL LPKNTPCLNA 
QEQFMSSLRP LAIQQIKAVS KSLISESSQP NTSSHNISVI ADLHLSTIDW EGTSFSNSPA 
IQRNTFSHDL KSEVESELSA IPDGFENIPE QLSCESERYT ANIKKVLDED SDGISPEEHL 
LSGITDLCLQ DLPLKERIFT KLSYPQDNLQ PDVNLKTLSI LSVKESCIAN SGSDCTSHLS 
KDLPGIPLQN ESRDSKILKG DQLLQEDYKV NTSVPYSVSN TVVKTCNVRP PNTALDHSRK 
VDMQTTRKIL MKKSVCLDRH SSDEQSAPVF GKAKYTTQRM KHSSQKHNSS HFKESGHNKL 
SSPKIHIKET EQCVRSYETA ENEESCFPDS TKSSLSSLQC HKKENNSGTC LDSPLPLRQR 
LKLRFQST