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Protein

Endonuclease III-like protein 1

Gene

NTHL1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.UniRule annotation17 Publications

Catalytic activityi

The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate.UniRule annotationBy similarity3 Publications

Cofactori

[4Fe-4S] clusterUniRule annotationNote: Binds 1 [4Fe-4S] cluster. The cluster does not appear to play a role in catalysis, but is probably involved in the proper positioning of the enzyme along the DNA strand.UniRule annotation

Enzyme regulationi

APE1 displaces NTHL1 from the N-glycosylase-generated AP site in DNA, thereby increasing the turnover of the DNA N-glycosylase activity. AP lyase activity is stimulated by YBX1.2 Publications

Kineticsi

  1. KM=371 nM for 5-hydroxy-6-hydrothymine containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  2. KM=1093 nM for 5-hydroxyuracil containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  3. KM=548 nM for 5-hydroxycytosine containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  4. KM=1101 nM for thymine glycol containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  5. KM=718 nM for 5,6-dihydroxycytosine containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  6. KM=0.05 nM for 5-hydroxycytosine-G containing duplex oligonucleotides (N-glycosylase activity)2 Publications
  7. KM=0.2 nM for 5-hydroxycytosine-A containing duplex oligonucleotides (N-glycosylase activity)2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei220Nucleophile; for N-glycosylase activityUniRule annotation1 Publication1
    Sitei239Important for catalytic activity1
    Metal bindingi290Iron-sulfur (4Fe-4S)UniRule annotation1
    Metal bindingi297Iron-sulfur (4Fe-4S)UniRule annotation1
    Metal bindingi300Iron-sulfur (4Fe-4S)UniRule annotation1
    Metal bindingi306Iron-sulfur (4Fe-4S)UniRule annotation1

    GO - Molecular functioni

    • 4 iron, 4 sulfur cluster binding Source: UniProtKB-HAMAP
    • DNA-(apurinic or apyrimidinic site) lyase activity Source: UniProtKB
    • DNA N-glycosylase activity Source: UniProtKB
    • double-stranded DNA binding Source: UniProtKB
    • endonuclease activity Source: ProtInc
    • metal ion binding Source: UniProtKB-KW
    • oxidized purine nucleobase lesion DNA N-glycosylase activity Source: Reactome
    • oxidized pyrimidine nucleobase lesion DNA N-glycosylase activity Source: GO_Central

    GO - Biological processi

    • base-excision repair, AP site formation Source: UniProtKB
    • depyrimidination Source: Reactome
    • nucleotide-excision repair, DNA incision, 5'-to lesion Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Glycosidase, Hydrolase, Lyase

    Keywords - Biological processi

    DNA damage, DNA repair

    Keywords - Ligandi

    4Fe-4S, Iron, Iron-sulfur, Metal-binding

    Enzyme and pathway databases

    BioCyciZFISH:HS00828-MONOMER.
    BRENDAi4.2.99.18. 2681.
    ReactomeiR-HSA-110328. Recognition and association of DNA glycosylase with site containing an affected pyrimidine.
    R-HSA-110329. Cleavage of the damaged pyrimidine.
    R-HSA-110357. Displacement of DNA glycosylase by APEX1.
    SABIO-RKP78549.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Endonuclease III-like protein 1UniRule annotation (EC:3.2.2.-UniRule annotation, EC:4.2.99.18UniRule annotation)
    Short name:
    hNTH1
    Alternative name(s):
    Bifunctional DNA N-glycosylase/DNA-(apurinic or apyrimidinic site) lyaseUniRule annotation
    Short name:
    DNA glycosylase/AP lyaseUniRule annotation
    Gene namesi
    Name:NTHL1UniRule annotation
    Synonyms:NTH1, OCTS3
    OrganismiHomo sapiens (Human)Imported
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 16

    Organism-specific databases

    HGNCiHGNC:8028. NTHL1.

    Subcellular locationi

    GO - Cellular componenti

    • mitochondrion Source: GO_Central
    • nucleoplasm Source: Reactome
    • nucleus Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Mitochondrion, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Familial adenomatous polyposis 3 (FAP3)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA form of familial adenomatous polyposis, a condition characterized by the development of multiple colorectal adenomatous polyps, benign neoplasms derived from glandular epithelium. Some affected individuals may develop colorectal carcinoma.
    See also OMIM:616415

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi40 – 42Missing : Sorted to the cytoplasm. 1 Publication3
    Mutagenesisi42R → A: Sorted to both nuclei and mitochondria. 1 Publication1
    Mutagenesisi42R → D: Sorted to the cytoplasm. 1 Publication1
    Mutagenesisi57R → A or D: Sorted to both nuclei and mitochondria. 1 Publication1
    Mutagenesisi220K → Q: Inactivates enzyme. 2 Publications1
    Mutagenesisi220K → R: 85-fold reduction in activity. Uncouples the glycosylase activity from the lyase activity. Shows glycosylase activity without any detectable AP-lyase activity during the first 10 min of the reaction. 2 Publications1

    Organism-specific databases

    DisGeNETi4913.
    MIMi616415. phenotype.
    OpenTargetsiENSG00000065057.
    PharmGKBiPA31811.

    Polymorphism and mutation databases

    BioMutaiNTHL1.
    DMDMi29840795.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 30MitochondrionUniRule annotation1 PublicationAdd BLAST30
    ChainiPRO_000010222731 – 312Endonuclease III-like protein 1Add BLAST282

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei71PhosphoserineCombined sources1
    Modified residuei73PhosphoserineCombined sources1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    EPDiP78549.
    MaxQBiP78549.
    PaxDbiP78549.
    PeptideAtlasiP78549.
    PRIDEiP78549.

    PTM databases

    iPTMnetiP78549.
    PhosphoSitePlusiP78549.

    Expressioni

    Tissue specificityi

    Widely expressed with highest levels in heart and lowest levels in lung and liver.2 Publications

    Developmental stagei

    Expression levels are regulated during the cell cycle with increased levels during early and mid S-phase.1 Publication

    Gene expression databases

    BgeeiENSG00000065057.
    CleanExiHS_NTHL1.
    ExpressionAtlasiP78549. baseline and differential.
    GenevisibleiP78549. HS.

    Organism-specific databases

    HPAiCAB025152.

    Interactioni

    Subunit structurei

    Interacts with YBX1.UniRule annotation1 Publication

    Protein-protein interaction databases

    BioGridi110968. 21 interactors.
    IntActiP78549. 4 interactors.
    STRINGi9606.ENSP00000219066.

    Structurei

    3D structure databases

    ProteinModelPortaliP78549.
    SMRiP78549.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini199 – 223HhHUniRule annotationAdd BLAST25

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi36 – 60Bipartite nuclear localization signalSequence analysisAdd BLAST25

    Sequence similaritiesi

    Belongs to the Nth/MutY family.UniRule annotation
    Contains 1 HhH domain.UniRule annotation

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG1921. Eukaryota.
    COG0177. LUCA.
    GeneTreeiENSGT00510000047513.
    HOGENOMiHOG000252209.
    HOVERGENiHBG052675.
    InParanoidiP78549.
    KOiK10773.
    OMAiWRNKVKY.
    OrthoDBiEOG091G0IVB.
    PhylomeDBiP78549.
    TreeFamiTF314967.

    Family and domain databases

    CDDicd00056. ENDO3c. 1 hit.
    Gene3Di1.10.1670.10. 1 hit.
    1.10.340.30. 1 hit.
    HAMAPiMF_03183. Endonuclease_III_Nth. 1 hit.
    InterProiIPR011257. DNA_glycosylase.
    IPR004036. Endonuclease-III-like_CS2.
    IPR003651. Endouclease3_FeS-loop_motif.
    IPR003265. HhH-GPD_domain.
    IPR000445. HhH_motif.
    IPR023170. HTH_base_excis_C.
    IPR030841. NTH1.
    [Graphical view]
    PfamiPF00633. HHH. 1 hit.
    PF00730. HhH-GPD. 1 hit.
    [Graphical view]
    SMARTiSM00478. ENDO3c. 1 hit.
    SM00525. FES. 1 hit.
    [Graphical view]
    SUPFAMiSSF48150. SSF48150. 1 hit.
    PROSITEiPS01155. ENDONUCLEASE_III_2. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative initiation. AlignAdd to basket

    Isoform 1 (identifier: P78549-1) [UniParc]FASTAAdd to basket
    Also known as: M-8

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MCSPQESGMT ALSARMLTRS RSLGPGAGPR GCREEPGPLR RREAAAEARK
    60 70 80 90 100
    SHSPVKRPRK AQRLRVAYEG SDSEKGEGAE PLKVPVWEPQ DWQQQLVNIR
    110 120 130 140 150
    AMRNKKDAPV DHLGTEHCYD SSAPPKVRRY QVLLSLMLSS QTKDQVTAGA
    160 170 180 190 200
    MQRLRARGLT VDSILQTDDA TLGKLIYPVG FWRSKVKYIK QTSAILQQHY
    210 220 230 240 250
    GGDIPASVAE LVALPGVGPK MAHLAMAVAW GTVSGIAVDT HVHRIANRLR
    260 270 280 290 300
    WTKKATKSPE ETRAALEEWL PRELWHEING LLVGFGQQTC LPVHPRCHAC
    310
    LNQALCPAAQ GL
    Length:312
    Mass (Da):34,390
    Last modified:May 1, 1999 - v2
    Checksum:i379816A1E0B45050
    GO
    Isoform 2 (identifier: P78549-2) [UniParc]FASTAAdd to basket
    Also known as: M+1

    The sequence of this isoform differs from the canonical sequence as follows:
         1-8: Missing.

    Show »
    Length:304
    Mass (Da):33,570
    Checksum:iDA97D508BE3D83F0
    GO
    Isoform 3 (identifier: P78549-3) [UniParc]FASTAAdd to basket
    Also known as: M+8

    The sequence of this isoform differs from the canonical sequence as follows:
         1-15: Missing.

    Show »
    Length:297
    Mass (Da):32,839
    Checksum:i5D531E41F9F27975
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti9 – 10MT → TS in CAA70865 (PubMed:10882850).Curated2
    Sequence conflicti78Missing in CAA70865 (PubMed:10882850).Curated1
    Sequence conflicti151M → I in AAB41534 (PubMed:8990169).Curated1
    Sequence conflicti160T → A in AAB41534 (PubMed:8990169).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_01612521R → W.1 PublicationCorresponds to variant rs3087469dbSNPEnsembl.1
    Natural variantiVAR_01612633R → K.Corresponds to variant rs2302172dbSNPEnsembl.1
    Natural variantiVAR_016127176I → T.Corresponds to variant rs1805378dbSNPEnsembl.1
    Natural variantiVAR_029318234S → L.1 PublicationCorresponds to variant rs3211977dbSNPEnsembl.1
    Natural variantiVAR_016128239D → Y.Corresponds to variant rs3087468dbSNPEnsembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0542921 – 15Missing in isoform 3. CuratedAdd BLAST15
    Alternative sequenceiVSP_0542931 – 8Missing in isoform 2. 4 Publications8

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U79718 mRNA. Translation: AAB41534.1.
    AB014460 Genomic DNA. Translation: BAA32695.1.
    AF498098 Genomic DNA. Translation: AAM11786.1.
    AC005600 Genomic DNA. Translation: AAC34209.1.
    AB001575 mRNA. Translation: BAA19413.1.
    U81285 mRNA. Translation: AAC51136.1.
    BC003014 mRNA. Translation: AAH03014.1.
    BC000391 mRNA. Translation: AAH00391.2.
    Y09687 mRNA. Translation: CAA70865.1.
    CCDSiCCDS10457.1. [P78549-1]
    RefSeqiNP_001305122.1. NM_001318193.1.
    NP_001305123.1. NM_001318194.1.
    NP_002519.1. NM_002528.6. [P78549-1]
    UniGeneiHs.66196.

    Genome annotation databases

    EnsembliENST00000219066; ENSP00000219066; ENSG00000065057. [P78549-1]
    GeneIDi4913.
    KEGGihsa:4913.
    UCSCiuc002col.1. human. [P78549-1]

    Keywords - Coding sequence diversityi

    Alternative initiation, Polymorphism

    Cross-referencesi

    Web resourcesi

    NIEHS-SNPs

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U79718 mRNA. Translation: AAB41534.1.
    AB014460 Genomic DNA. Translation: BAA32695.1.
    AF498098 Genomic DNA. Translation: AAM11786.1.
    AC005600 Genomic DNA. Translation: AAC34209.1.
    AB001575 mRNA. Translation: BAA19413.1.
    U81285 mRNA. Translation: AAC51136.1.
    BC003014 mRNA. Translation: AAH03014.1.
    BC000391 mRNA. Translation: AAH00391.2.
    Y09687 mRNA. Translation: CAA70865.1.
    CCDSiCCDS10457.1. [P78549-1]
    RefSeqiNP_001305122.1. NM_001318193.1.
    NP_001305123.1. NM_001318194.1.
    NP_002519.1. NM_002528.6. [P78549-1]
    UniGeneiHs.66196.

    3D structure databases

    ProteinModelPortaliP78549.
    SMRiP78549.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi110968. 21 interactors.
    IntActiP78549. 4 interactors.
    STRINGi9606.ENSP00000219066.

    PTM databases

    iPTMnetiP78549.
    PhosphoSitePlusiP78549.

    Polymorphism and mutation databases

    BioMutaiNTHL1.
    DMDMi29840795.

    Proteomic databases

    EPDiP78549.
    MaxQBiP78549.
    PaxDbiP78549.
    PeptideAtlasiP78549.
    PRIDEiP78549.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000219066; ENSP00000219066; ENSG00000065057. [P78549-1]
    GeneIDi4913.
    KEGGihsa:4913.
    UCSCiuc002col.1. human. [P78549-1]

    Organism-specific databases

    CTDi4913.
    DisGeNETi4913.
    GeneCardsiNTHL1.
    HGNCiHGNC:8028. NTHL1.
    HPAiCAB025152.
    MIMi602656. gene.
    616415. phenotype.
    neXtProtiNX_P78549.
    OpenTargetsiENSG00000065057.
    PharmGKBiPA31811.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG1921. Eukaryota.
    COG0177. LUCA.
    GeneTreeiENSGT00510000047513.
    HOGENOMiHOG000252209.
    HOVERGENiHBG052675.
    InParanoidiP78549.
    KOiK10773.
    OMAiWRNKVKY.
    OrthoDBiEOG091G0IVB.
    PhylomeDBiP78549.
    TreeFamiTF314967.

    Enzyme and pathway databases

    BioCyciZFISH:HS00828-MONOMER.
    BRENDAi4.2.99.18. 2681.
    ReactomeiR-HSA-110328. Recognition and association of DNA glycosylase with site containing an affected pyrimidine.
    R-HSA-110329. Cleavage of the damaged pyrimidine.
    R-HSA-110357. Displacement of DNA glycosylase by APEX1.
    SABIO-RKP78549.

    Miscellaneous databases

    GeneWikiiNTHL1.
    GenomeRNAii4913.
    PROiP78549.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000065057.
    CleanExiHS_NTHL1.
    ExpressionAtlasiP78549. baseline and differential.
    GenevisibleiP78549. HS.

    Family and domain databases

    CDDicd00056. ENDO3c. 1 hit.
    Gene3Di1.10.1670.10. 1 hit.
    1.10.340.30. 1 hit.
    HAMAPiMF_03183. Endonuclease_III_Nth. 1 hit.
    InterProiIPR011257. DNA_glycosylase.
    IPR004036. Endonuclease-III-like_CS2.
    IPR003651. Endouclease3_FeS-loop_motif.
    IPR003265. HhH-GPD_domain.
    IPR000445. HhH_motif.
    IPR023170. HTH_base_excis_C.
    IPR030841. NTH1.
    [Graphical view]
    PfamiPF00633. HHH. 1 hit.
    PF00730. HhH-GPD. 1 hit.
    [Graphical view]
    SMARTiSM00478. ENDO3c. 1 hit.
    SM00525. FES. 1 hit.
    [Graphical view]
    SUPFAMiSSF48150. SSF48150. 1 hit.
    PROSITEiPS01155. ENDONUCLEASE_III_2. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiNTH_HUMAN
    AccessioniPrimary (citable) accession number: P78549
    Secondary accession number(s): Q1MVR1
    , Q99566, Q99794, Q9BPX2
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 28, 2003
    Last sequence update: May 1, 1999
    Last modified: November 30, 2016
    This is version 161 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 16
      Human chromosome 16: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.