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    GEN1 GEN1 Holliday junction 5' flap endonuclease [ Homo sapiens (human) ]

    Gene ID: 348654, updated on 9-Dec-2024

    Summary

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    Official Symbol
    GEN1provided by HGNC
    Official Full Name
    GEN1 Holliday junction 5' flap endonucleaseprovided by HGNC
    Primary source
    HGNC:HGNC:26881
    See related
    Ensembl:ENSG00000178295 MIM:612449; AllianceGenome:HGNC:26881
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    Gen
    Summary
    This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]
    Expression
    Broad expression in lymph node (RPKM 4.2), testis (RPKM 3.9) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See GEN1 in Genome Data Viewer
    Location:
    2p24.2
    Exon count:
    19
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (17753278..17788946)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (17785078..17820679)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (17935136..17970213)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene nascent polypeptide associated complex subunit alpha pseudogene Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr2:17699235-17700434 Neighboring gene RAD51 associated protein 2 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15351 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr2:17724689-17725200 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr2:17725201-17725712 Neighboring gene visinin like 1 Neighboring gene OCT4-NANOG-H3K4me1 hESC enhancer GRCh37_chr2:17760843-17761612 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr2:17771124-17772061 Neighboring gene uncharacterized LOC124908054 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:17825464-17826251 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15352 Neighboring gene structural maintenance of chromosomes 6 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr2:17929152-17929835 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11189 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11190 Neighboring gene uncharacterized LOC105373449 Neighboring gene Sharpr-MPRA regulatory region 14936 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15353 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15354 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15355 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15356 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr2:18008377-18009074 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:18011228-18011728 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11191 Neighboring gene uncharacterized LOC112267888 Neighboring gene mesogenin 1 Neighboring gene zona pellucida glycoprotein AX, pseudogene

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Resolution of the Holliday junction recombination intermediate by human GEN1 at the single-molecule level. Sobhy MA, et al. Nucleic Acids Res, 2019 Feb 28. PMID 30590761, Free PMC Article
    2. GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract. Du X, et al. Hum Genomics, 2024 Apr 24. PMID 38654324, Free PMC Article
    3. Reverse Transcription-PCR-based Sanger Sequencing-confirmed Exon-skipping Effect of a Novel GEN1 Intronic Variant (c.1408+4A>G). Kim J, et al. Ann Lab Med, 2024 Mar 1. PMID 37840312, Free PMC Article
    4. The human Holliday junction resolvase GEN1 rescues the meiotic phenotype of a Schizosaccharomyces pombe mus81 mutant. Lorenz A, et al. Nucleic Acids Res, 2010 Apr. PMID 20040574, Free PMC Article
    5. Mutation and association analysis of GEN1 in breast cancer susceptibility. Turnbull C, et al. Breast Cancer Res Treat, 2010 Nov. PMID 20512659, Free PMC Article

    See all (52) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.
      Title: GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.
    2. Reverse Transcription-PCR-based Sanger Sequencing-confirmed Exon-skipping Effect of a Novel GEN1 Intronic Variant (c.1408+4A>G).
      Title: Reverse Transcription-PCR-based Sanger Sequencing-confirmed Exon-skipping Effect of a Novel GEN1 Intronic Variant (c.1408+4A>G).
    3. NCAPH Stabilizes GEN1 in Chromatin to Resolve Ultra-Fine DNA Bridges and Maintain Chromosome Stability.
      Title: NCAPH Stabilizes GEN1 in Chromatin to Resolve Ultra-Fine DNA Bridges and Maintain Chromosome Stability.
    4. The tight binding of GEN1 monomer to intact- and singly-cleaved Holliday junctions empowers it as the last resort to process Holliday junctions that escape the primary mechanisms
      Title: Resolution of the Holliday junction recombination intermediate by human GEN1 at the single-molecule level.
    5. Using RNAi or FA-P cells complemented with SLX4 mutants that abrogate interaction with MUS81 or SLX1, we show that SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised forks by GEN1.
      Title: SLX4 Prevents GEN1-Dependent DSBs During DNA Replication Arrest Under Pathological Conditions in Human Cells.
    6. GEN1 efficiently cleaves both single and double Holliday junctions contained within large recombination intermediates. Moreover, we find that GEN1 exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA.
      Title: Resolution of single and double Holliday junction recombination intermediates by GEN1.
    7. the in vitro activities of DmGen and HsGEN1 are strikingly similar.
      Title: Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates.
    8. Data suggest that dimeric GEN1 binds with high affinity/selectivity to Holliday junctions, introducing two symmetrical hydrolytic cleavages of phosphodiester backbone; at present, less is known about SLX1-SLX4-MUS81-EME1 resolving enzyme complex. (GEN1 = Holliday junction 5' flap endonuclease; SLX = structure-specific endonuclease subunit; MUS81 = MUS81 endonuclease; EME1 = essential meiotic endonuclease 1) [REVIEW]
      Title: Holliday junction-resolving enzymes-structures and mechanisms.
    9. human GEN1 protein promotes Holliday junction resolution by a mechanism that is analogous to that exhibited by the prototypic HJ resolvase E. coli RuvC.
      Title: GEN1 promotes Holliday junction resolution by a coordinated nick and counter-nick mechanism.
    10. GEN1 is controlled by nuclear exclusion, driven by a nuclear export signal that restricts GEN1 actions to mitosis. Spatial control of GEN1 contributes to genome stability by avoiding competition with non-crossover promoting repair pathways.
      Title: Spatial control of the GEN1 Holliday junction resolvase ensures genome stability.
    Submit: New GeneRIF Correction See all GeneRIFs (21)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2021-02-02)

    ClinGen Genome Curation Page
    Haploinsufficency

    Dosage sensitivity unlikely (Last evaluated 2021-02-02)

    ClinGen Genome Curation PagePubMed

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ36312, FLJ40869, DKFZp781F0986

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables 5'-flap endonuclease activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables 5'-flap endonuclease activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables crossover junction DNA endonuclease activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables crossover junction DNA endonuclease activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables four-way junction DNA binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables four-way junction DNA binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables magnesium ion binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables protein homodimerization activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in double-strand break repair via homologous recombination IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in positive regulation of mitotic cell cycle spindle assembly checkpoint IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in regulation of centrosome duplication IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in replication fork processing IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in resolution of DNA recombination intermediates IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in resolution of mitotic recombination intermediates IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in centrosome IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    flap endonuclease GEN homolog 1
    Names
    Gen endonuclease homolog 1
    Holliday junction resolvase

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_051292.2 RefSeqGene

      Range
      5862..40670
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001130009.3 → NP_001123481.3  flap endonuclease GEN homolog 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Variants 1 and 2 encode the same protein.
      Source sequence(s)
      AC093731, AC097377
      Consensus CDS
      CCDS1691.1
      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Related
      ENSP00000370653.2, ENST00000381254.7
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    2. NM_182625.5 → NP_872431.5  flap endonuclease GEN homolog 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the shorter transcript. Variants 1 and 2 encode the same protein.
      Source sequence(s)
      AC093731, AC097377
      Consensus CDS
      CCDS1691.1
      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Related
      ENSP00000318977.7, ENST00000317402.11
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      17753278..17788946
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011532822.3 → XP_011531124.1  flap endonuclease GEN homolog 1 isoform X1

      See identical proteins and their annotated locations for XP_011531124.1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    2. XM_011532820.3 → XP_011531122.1  flap endonuclease GEN homolog 1 isoform X1

      See identical proteins and their annotated locations for XP_011531122.1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    3. XM_006712005.4 → XP_006712068.1  flap endonuclease GEN homolog 1 isoform X1

      See identical proteins and their annotated locations for XP_006712068.1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    4. XM_047444147.1 → XP_047300103.1  flap endonuclease GEN homolog 1 isoform X1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37

    5. XM_011532821.3 → XP_011531123.1  flap endonuclease GEN homolog 1 isoform X1

      See identical proteins and their annotated locations for XP_011531123.1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    6. XM_005262613.5 → XP_005262670.1  flap endonuclease GEN homolog 1 isoform X1

      See identical proteins and their annotated locations for XP_005262670.1

      UniProtKB/Swiss-Prot
      Q17RS7, Q17RS9, Q6ZN37
      Conserved Domains (3) summary
      cd09905
      Location:195 → 338
      H3TH_GEN1; H3TH domain of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease
      cd09869
      Location:2 → 206
      PIN_GEN1; FEN-like PIN domains of Gap Endonuclease 1, a structure-specific, divalent-metal-ion dependent, 5' nuclease and homologs
      pfam18704
      Location:398 → 458
      Chromo_2; Chromatin organization modifier domain 2

    7. XM_047444156.1 → XP_047300112.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    8. XM_047444157.1 → XP_047300113.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    9. XM_047444155.1 → XP_047300111.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    10. XM_047444158.1 → XP_047300114.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    11. XM_047444159.1 → XP_047300115.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      17785078..17820679
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054341774.1 → XP_054197749.1  flap endonuclease GEN homolog 1 isoform X1

    2. XM_054341770.1 → XP_054197745.1  flap endonuclease GEN homolog 1 isoform X1

    3. XM_054341772.1 → XP_054197747.1  flap endonuclease GEN homolog 1 isoform X1

    4. XM_054341775.1 → XP_054197750.1  flap endonuclease GEN homolog 1 isoform X1

    5. XM_054341771.1 → XP_054197746.1  flap endonuclease GEN homolog 1 isoform X1

    6. XM_054341773.1 → XP_054197748.1  flap endonuclease GEN homolog 1 isoform X1

    7. XM_054341777.1 → XP_054197752.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    8. XM_054341778.1 → XP_054197753.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    9. XM_054341776.1 → XP_054197751.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    10. XM_054341779.1 → XP_054197754.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6

    11. XM_054341780.1 → XP_054197755.1  flap endonuclease GEN homolog 1 isoform X2

      UniProtKB/TrEMBL
      Q8N1H6
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q17RS7.2 GenPept UniProtKB/Swiss-Prot:Q17RS7

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