NTH_HUMAN
ID NTH_HUMAN Reviewed; 312 AA.
AC P78549; Q1MVR1; Q99566; Q99794; Q9BPX2;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Endonuclease III-like protein 1 {ECO:0000255|HAMAP-Rule:MF_03183};
DE Short=hNTH1;
DE EC=3.2.2.- {ECO:0000255|HAMAP-Rule:MF_03183, ECO:0000269|PubMed:9927729};
DE EC=4.2.99.18 {ECO:0000255|HAMAP-Rule:MF_03183, ECO:0000269|PubMed:9927729};
DE AltName: Full=Bifunctional DNA N-glycosylase/DNA-(apurinic or apyrimidinic site) lyase {ECO:0000255|HAMAP-Rule:MF_03183};
DE Short=DNA glycosylase/AP lyase {ECO:0000255|HAMAP-Rule:MF_03183};
DE Flags: Precursor;
GN Name=NTHL1 {ECO:0000255|HAMAP-Rule:MF_03183}; Synonyms=NTH1, OCTS3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAM11786.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=8990169; DOI=10.1073/pnas.94.1.109;
RA Aspinwall R., Rothwell D.G., Roldan-Arjona T., Anselmino C., Ward C.J.,
RA Cheadle J.P., Sampson J.R., Lindahl T., Harris P.C., Hickson I.D.;
RT "Cloning and characterization of a functional human homolog of Escherichia
RT coli endonuclease III.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:109-114(1997).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 2), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=9831664; DOI=10.1016/s0378-1119(98)00485-5;
RA Imai K., Sarker A.H., Akiyama K., Ikeda S., Yao M., Tsutsui K.,
RA Shohmori T., Seki S.;
RT "Genomic structure and sequence of a human homologue (NTHL1/NTH1) of
RT Escherichia coli endonuclease III with those of the adjacent parts of TSC2
RT and SLC9A3R2 genes.";
RL Gene 222:287-295(1998).
RN [3] {ECO:0000305, ECO:0000312|EMBL:AAM11786.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS TRP-21 AND LEU-234.
RG NIEHS SNPs program;
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, ACTIVE SITE, AND
RP MUTAGENESIS OF LYS-220.
RC TISSUE=Bone marrow;
RX PubMed=9705289; DOI=10.1074/jbc.273.34.21585;
RA Ikeda S., Biswas T., Roy R., Izumi T., Boldogh I., Kurosky A., Sarker A.H.,
RA Seki S., Mitra S.;
RT "Purification and characterization of human NTH1, a homolog of Escherichia
RT coli endonuclease III. Direct identification of Lys-212 as the active
RT nucleophilic residue.";
RL J. Biol. Chem. 273:21585-21593(1998).
RN [6] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND FUNCTION.
RC TISSUE=Spleen;
RX PubMed=9045706; DOI=10.1074/jbc.272.10.6733;
RA Hilbert T.P., Chaung W., Boorstein R.J., Cunningham R.P., Teebor G.W.;
RT "Cloning and expression of the cDNA encoding the human homologue of the DNA
RT repair enzyme, Escherichia coli endonuclease III.";
RL J. Biol. Chem. 272:6733-6740(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 8-312 (ISOFORMS 1 AND 2).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-312, FUNCTION, SUBCELLULAR LOCATION, AND
RP DEVELOPMENTAL STAGE.
RX PubMed=10882850; DOI=10.1016/s0921-8777(00)00015-x;
RA Luna L., Bjoras M., Hoff E., Rognes T., Seeberg E.;
RT "Cell-cycle regulation, intracellular sorting and induced overexpression of
RT the human NTH1 DNA glycosylase involved in removal of formamidopyrimidine
RT residues from DNA.";
RL Mutat. Res. 460:95-104(2000).
RN [9]
RP PROTEIN SEQUENCE OF 31-37; 48-56; 61-78; 107-113; 120-126 AND 221-227,
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12144783; DOI=10.1016/s0022-2836(02)00623-x;
RA Liu X., Roy R.;
RT "Truncation of amino-terminal tail stimulates activity of human
RT endonuclease III (hNTH1).";
RL J. Mol. Biol. 321:265-276(2002).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=9611236; DOI=10.1093/nar/26.12.2917;
RA Takao M., Aburatani H., Kobayashi K., Yasui A.;
RT "Mitochondrial targeting of human DNA glycosylases for repair of oxidative
RT DNA damage.";
RL Nucleic Acids Res. 26:2917-2922(1998).
RN [11]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=9890904; DOI=10.1021/bi9819071;
RA Dizdaroglu M., Karahalil B., Senturker S., Buckley T.J., Roldan-Arjona T.;
RT "Excision of products of oxidative DNA base damage by human NTH1 protein.";
RL Biochemistry 38:243-246(1999).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND INTERACTION WITH
RP ERCC5.
RX PubMed=9927729; DOI=10.1093/nar/27.4.979;
RA Bessho T.;
RT "Nucleotide excision repair 3' endonuclease XPG stimulates the activity of
RT base excision repair enzyme thymine glycol DNA glycosylase.";
RL Nucleic Acids Res. 27:979-983(1999).
RN [13]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11380260; DOI=10.1021/bi0028901;
RA Eide L., Luna L., Gustad E.C., Henderson P.T., Essigmann J.M., Demple B.,
RA Seeberg E.;
RT "Human endonuclease III acts preferentially on DNA damage opposite guanine
RT residues in DNA.";
RL Biochemistry 40:6653-6659(2001).
RN [14]
RP FUNCTION, AND MUTAGENESIS OF LYS-220.
RX PubMed=11695910; DOI=10.1021/bi011053b;
RA Liu X., Roy R.;
RT "Mutation at active site lysine 212 to arginine uncouples the glycosylase
RT activity from the lyase activity of human endonuclease III.";
RL Biochemistry 40:13617-13622(2001).
RN [15]
RP CATALYTIC ACTIVITY, INTERACTION WITH YBX1, AND ACTIVITY REGULATION.
RX PubMed=11287425; DOI=10.1074/jbc.m101594200;
RA Marenstein D.R., Ocampo M.T., Chan M.K., Altamirano A., Basu A.K.,
RA Boorstein R.J., Cunningham R.P., Teebor G.W.;
RT "Stimulation of human endonuclease III by Y box-binding protein 1 (DNA-
RT binding protein B). Interaction between a base excision repair enzyme and a
RT transcription factor.";
RL J. Biol. Chem. 276:21242-21249(2001).
RN [16]
RP FUNCTION.
RX PubMed=11328882; DOI=10.1093/nar/29.9.1975;
RA Matsumoto Y., Zhang Q.M., Takao M., Yasui A., Yonei S.;
RT "Escherichia coli Nth and human hNTH1 DNA glycosylases are involved in
RT removal of 8-oxoguanine from 8-oxoguanine/guanine mispairs in DNA.";
RL Nucleic Acids Res. 29:1975-1981(2001).
RN [17] {ECO:0000305}
RP SUBCELLULAR LOCATION, ALTERNATIVE INITIATION, AND MUTAGENESIS OF
RP 40-ARG--ARG-42; ARG-42 AND ARG-57.
RX PubMed=12531031; DOI=10.1016/s1568-7864(02)00145-3;
RA Ikeda S., Kohmoto T., Tabata R., Seki Y.;
RT "Differential intracellular localization of the human and mouse
RT endonuclease III homologs and analysis of the sorting signals.";
RL DNA Repair 1:847-854(2002).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12140329; DOI=10.1093/nar/gkf460;
RA Miyabe I., Zhang Q.M., Kino K., Sugiyama H., Takao M., Yasui A., Yonei S.;
RT "Identification of 5-formyluracil DNA glycosylase activity of human hNTH1
RT protein.";
RL Nucleic Acids Res. 30:3443-3448(2002).
RN [19]
RP FUNCTION, SUBSTRATES, AND ACTIVITY REGULATION.
RX PubMed=12519758; DOI=10.1074/jbc.m212168200;
RA Marenstein D.R., Chan M.K., Altamirano A., Basu A.K., Boorstein R.J.,
RA Cunningham R.P., Teebor G.W.;
RT "Substrate specificity of human endonuclease III (hNTH1). Effect of human
RT APE1 on hNTH1 activity.";
RL J. Biol. Chem. 278:9005-9012(2003).
RN [20]
RP FUNCTION, AND SUBSTRATES.
RX PubMed=14734554; DOI=10.1074/jbc.m400393200;
RA Katafuchi A., Nakano T., Masaoka A., Terato H., Iwai S., Hanaoka F.,
RA Ide H.;
RT "Differential specificity of human and Escherichia coli endonuclease III
RT and VIII homologues for oxidative base lesions.";
RL J. Biol. Chem. 279:14464-14471(2004).
RN [21]
RP FUNCTION, AND SUBSTRATES.
RX PubMed=15533839; DOI=10.1016/j.dnarep.2004.08.002;
RA Zhang Q.M., Yonekura S., Takao M., Yasui A., Sugiyama H., Yonei S.;
RT "DNA glycosylase activities for thymine residues oxidized in the methyl
RT group are functions of the hNEIL1 and hNTH1 enzymes in human cells.";
RL DNA Repair 4:71-79(2005).
RN [22]
RP FUNCTION.
RX PubMed=17923696; DOI=10.1128/mcb.00791-07;
RA Prasad A., Wallace S.S., Pederson D.S.;
RT "Initiation of base excision repair of oxidative lesions in nucleosomes by
RT the human, bifunctional DNA glycosylase NTH1.";
RL Mol. Cell. Biol. 27:8442-8453(2007).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP FUNCTION.
RX PubMed=20005182; DOI=10.1016/j.dnarep.2009.11.005;
RA Odell I.D., Newick K., Heintz N.H., Wallace S.S., Pederson D.S.;
RT "Non-specific DNA binding interferes with the efficient excision of
RT oxidative lesions from chromatin by the human DNA glycosylase, NEIL1.";
RL DNA Repair 9:134-143(2010).
RN [25]
RP FUNCTION.
RX PubMed=20110254; DOI=10.1093/nar/gkq022;
RA Matsumoto N., Toga T., Hayashi R., Sugasawa K., Katayanagi K., Ide H.,
RA Kuraoka I., Iwai S.;
RT "Fluorescent probes for the analysis of DNA strand scission in base
RT excision repair.";
RL Nucleic Acids Res. 38:E101-E101(2010).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [27]
RP FUNCTION.
RX PubMed=21930793; DOI=10.1128/mcb.05715-11;
RA Odell I.D., Barbour J.E., Murphy D.L., Della-Maria J.A., Sweasy J.B.,
RA Tomkinson A.E., Wallace S.S., Pederson D.S.;
RT "Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base
RT excision repair.";
RL Mol. Cell. Biol. 31:4623-4632(2011).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71 AND SER-73, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [30]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [31]
RP INVOLVEMENT IN FAP3.
RX PubMed=25938944; DOI=10.1038/ng.3287;
RA Weren R.D., Ligtenberg M.J., Kets C.M., de Voer R.M., Verwiel E.T.,
RA Spruijt L., van Zelst-Stams W.A., Jongmans M.C., Gilissen C.,
RA Hehir-Kwa J.Y., Hoischen A., Shendure J., Boyle E.A., Kamping E.J.,
RA Nagtegaal I.D., Tops B.B., Nagengast F.M., Geurts van Kessel A.,
RA van Krieken J.H., Kuiper R.P., Hoogerbrugge N.;
RT "A germline homozygous mutation in the base-excision repair gene NTHL1
RT causes adenomatous polyposis and colorectal cancer.";
RL Nat. Genet. 47:668-671(2015).
CC -!- FUNCTION: Bifunctional DNA N-glycosylase with associated
CC apurinic/apyrimidinic (AP) lyase function that catalyzes the first step
CC in base excision repair (BER), the primary repair pathway for the
CC repair of oxidative DNA damage (PubMed:9927729). The DNA N-glycosylase
CC activity releases the damaged DNA base from DNA by cleaving the N-
CC glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the
CC phosphodiester bond 3' to the AP site by a beta-elimination. Primarily
CC recognizes and repairs oxidative base damage of pyrimidines. Has also
CC 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts
CC preferentially on DNA damage opposite guanine residues in DNA. Is able
CC to process lesions in nucleosomes without requiring or inducing
CC nucleosome disruption. {ECO:0000255|HAMAP-Rule:MF_03183,
CC ECO:0000269|PubMed:10882850, ECO:0000269|PubMed:11328882,
CC ECO:0000269|PubMed:11380260, ECO:0000269|PubMed:11695910,
CC ECO:0000269|PubMed:12140329, ECO:0000269|PubMed:12144783,
CC ECO:0000269|PubMed:12519758, ECO:0000269|PubMed:14734554,
CC ECO:0000269|PubMed:15533839, ECO:0000269|PubMed:17923696,
CC ECO:0000269|PubMed:20005182, ECO:0000269|PubMed:20110254,
CC ECO:0000269|PubMed:21930793, ECO:0000269|PubMed:8990169,
CC ECO:0000269|PubMed:9045706, ECO:0000269|PubMed:9705289,
CC ECO:0000269|PubMed:9890904, ECO:0000269|PubMed:9927729}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2'-deoxyribonucleotide-(2'-deoxyribose 5'-phosphate)-2'-
CC deoxyribonucleotide-DNA = a 3'-end 2'-deoxyribonucleotide-(2,3-
CC dehydro-2,3-deoxyribose 5'-phosphate)-DNA + a 5'-end 5'-monophospho-
CC 2'-deoxyribonucleoside-DNA + H(+); Xref=Rhea:RHEA:66592, Rhea:RHEA-
CC COMP:13180, Rhea:RHEA-COMP:16897, Rhea:RHEA-COMP:17067,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:136412, ChEBI:CHEBI:157695,
CC ChEBI:CHEBI:167181; EC=4.2.99.18; Evidence={ECO:0000255|HAMAP-
CC Rule:MF_03183, ECO:0000269|PubMed:11287425,
CC ECO:0000269|PubMed:12140329, ECO:0000269|PubMed:12144783,
CC ECO:0000269|PubMed:9927729};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03183};
CC Note=Binds 1 [4Fe-4S] cluster. The cluster does not appear to play a
CC role in catalysis, but is probably involved in the proper positioning
CC of the enzyme along the DNA strand. {ECO:0000255|HAMAP-Rule:MF_03183};
CC -!- ACTIVITY REGULATION: APE1 displaces NTHL1 from the N-glycosylase-
CC generated AP site in DNA, thereby increasing the turnover of the DNA N-
CC glycosylase activity (PubMed:11287425, PubMed:12519758). AP lyase
CC activity is stimulated by YBX1 (PubMed:11287425). ERCC5/XPG stimulates
CC NTHL1 activity and NTHL1 binding to its DNA substrate (PubMed:9927729).
CC {ECO:0000269|PubMed:11287425, ECO:0000269|PubMed:12519758,
CC ECO:0000269|PubMed:9927729}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=371 nM for 5-hydroxy-6-hydrothymine containing duplex
CC oligonucleotides (N-glycosylase activity)
CC {ECO:0000269|PubMed:11380260, ECO:0000269|PubMed:9890904};
CC KM=1093 nM for 5-hydroxyuracil containing duplex oligonucleotides (N-
CC glycosylase activity) {ECO:0000269|PubMed:11380260,
CC ECO:0000269|PubMed:9890904};
CC KM=548 nM for 5-hydroxycytosine containing duplex oligonucleotides
CC (N-glycosylase activity) {ECO:0000269|PubMed:11380260,
CC ECO:0000269|PubMed:9890904};
CC KM=1101 nM for thymine glycol containing duplex oligonucleotides (N-
CC glycosylase activity) {ECO:0000269|PubMed:11380260,
CC ECO:0000269|PubMed:9890904};
CC KM=718 nM for 5,6-dihydroxycytosine containing duplex
CC oligonucleotides (N-glycosylase activity)
CC {ECO:0000269|PubMed:11380260, ECO:0000269|PubMed:9890904};
CC KM=0.05 nM for 5-hydroxycytosine-G containing duplex oligonucleotides
CC (N-glycosylase activity) {ECO:0000269|PubMed:11380260,
CC ECO:0000269|PubMed:9890904};
CC KM=0.2 nM for 5-hydroxycytosine-A containing duplex oligonucleotides
CC (N-glycosylase activity) {ECO:0000269|PubMed:11380260,
CC ECO:0000269|PubMed:9890904};
CC -!- SUBUNIT: Interacts with YBX1 (By similarity) (PubMed:11287425).
CC Interacts with ERCC5/XPG; the interaction stimulates NTHL1 activity and
CC NTHL1 binding to its DNA substrate (PubMed:9927729).
CC {ECO:0000255|HAMAP-Rule:MF_03183, ECO:0000269|PubMed:11287425,
CC ECO:0000269|PubMed:9927729}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03183,
CC ECO:0000269|PubMed:10882850, ECO:0000269|PubMed:12531031,
CC ECO:0000269|PubMed:9611236}. Mitochondrion {ECO:0000255|HAMAP-
CC Rule:MF_03183, ECO:0000269|PubMed:9611236}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=3;
CC Name=1; Synonyms=M-8;
CC IsoId=P78549-1; Sequence=Displayed;
CC Name=2; Synonyms=M+1;
CC IsoId=P78549-2; Sequence=VSP_054293;
CC Name=3; Synonyms=M+8;
CC IsoId=P78549-3; Sequence=VSP_054292;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in heart and
CC lowest levels in lung and liver. {ECO:0000269|PubMed:8990169,
CC ECO:0000269|PubMed:9831664}.
CC -!- DEVELOPMENTAL STAGE: Expression levels are regulated during the cell
CC cycle with increased levels during early and mid S-phase.
CC {ECO:0000269|PubMed:10882850}.
CC -!- DISEASE: Familial adenomatous polyposis 3 (FAP3) [MIM:616415]: A form
CC of familial adenomatous polyposis, a condition characterized by the
CC development of multiple colorectal adenomatous polyps, benign neoplasms
CC derived from glandular epithelium. Some affected individuals may
CC develop colorectal carcinoma. {ECO:0000269|PubMed:25938944}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the Nth/MutY family. {ECO:0000255|HAMAP-
CC Rule:MF_03183}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nthl1/";
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DR EMBL; U79718; AAB41534.1; -; mRNA.
DR EMBL; AB014460; BAA32695.1; -; Genomic_DNA.
DR EMBL; AF498098; AAM11786.1; -; Genomic_DNA.
DR EMBL; AC005600; AAC34209.1; -; Genomic_DNA.
DR EMBL; AB001575; BAA19413.1; -; mRNA.
DR EMBL; U81285; AAC51136.1; -; mRNA.
DR EMBL; BC003014; AAH03014.1; -; mRNA.
DR EMBL; BC000391; AAH00391.2; -; mRNA.
DR EMBL; Y09687; CAA70865.1; -; mRNA.
DR CCDS; CCDS10457.1; -. [P78549-2]
DR RefSeq; NP_001305122.1; NM_001318193.1.
DR RefSeq; NP_001305123.1; NM_001318194.1.
DR RefSeq; NP_002519.1; NM_002528.6. [P78549-2]
DR PDB; 7RDS; X-ray; 2.50 A; A=64-312.
DR PDB; 7RDT; X-ray; 2.10 A; A=64-109, A=125-312.
DR PDBsum; 7RDS; -.
DR PDBsum; 7RDT; -.
DR AlphaFoldDB; P78549; -.
DR SMR; P78549; -.
DR BioGRID; 110968; 42.
DR IntAct; P78549; 9.
DR STRING; 9606.ENSP00000219066; -.
DR ChEMBL; CHEMBL4523264; -.
DR iPTMnet; P78549; -.
DR PhosphoSitePlus; P78549; -.
DR BioMuta; NTHL1; -.
DR DMDM; 29840795; -.
DR EPD; P78549; -.
DR jPOST; P78549; -.
DR MassIVE; P78549; -.
DR MaxQB; P78549; -.
DR PaxDb; P78549; -.
DR PeptideAtlas; P78549; -.
DR PRIDE; P78549; -.
DR ProteomicsDB; 57648; -. [P78549-1]
DR Antibodypedia; 23443; 256 antibodies from 28 providers.
DR DNASU; 4913; -.
DR Ensembl; ENST00000219066.5; ENSP00000219066.1; ENSG00000065057.9. [P78549-1]
DR Ensembl; ENST00000651570.2; ENSP00000498421.1; ENSG00000065057.9. [P78549-2]
DR GeneID; 4913; -.
DR KEGG; hsa:4913; -.
DR MANE-Select; ENST00000651570.2; ENSP00000498421.1; NM_002528.7; NP_002519.2. [P78549-2]
DR UCSC; uc002col.1; human. [P78549-1]
DR CTD; 4913; -.
DR DisGeNET; 4913; -.
DR GeneCards; NTHL1; -.
DR GeneReviews; NTHL1; -.
DR HGNC; HGNC:8028; NTHL1.
DR HPA; ENSG00000065057; Low tissue specificity.
DR MalaCards; NTHL1; -.
DR MIM; 602656; gene.
DR MIM; 616415; phenotype.
DR neXtProt; NX_P78549; -.
DR OpenTargets; ENSG00000065057; -.
DR Orphanet; 454840; NTHL1-related attenuated familial adenomatous polyposis.
DR PharmGKB; PA31811; -.
DR VEuPathDB; HostDB:ENSG00000065057; -.
DR eggNOG; KOG1921; Eukaryota.
DR GeneTree; ENSGT00510000047513; -.
DR HOGENOM; CLU_012862_4_2_1; -.
DR InParanoid; P78549; -.
DR OMA; WQQFTHL; -.
DR OrthoDB; 1322642at2759; -.
DR PhylomeDB; P78549; -.
DR TreeFam; TF314967; -.
DR BRENDA; 4.2.99.18; 2681.
DR PathwayCommons; P78549; -.
DR Reactome; R-HSA-110328; Recognition and association of DNA glycosylase with site containing an affected pyrimidine.
DR Reactome; R-HSA-110329; Cleavage of the damaged pyrimidine.
DR Reactome; R-HSA-110357; Displacement of DNA glycosylase by APEX1.
DR Reactome; R-HSA-9630221; Defective NTHL1 substrate processing.
DR Reactome; R-HSA-9630222; Defective NTHL1 substrate binding.
DR SABIO-RK; P78549; -.
DR SignaLink; P78549; -.
DR BioGRID-ORCS; 4913; 12 hits in 1086 CRISPR screens.
DR GeneWiki; NTHL1; -.
DR GenomeRNAi; 4913; -.
DR Pharos; P78549; Tbio.
DR PRO; PR:P78549; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P78549; protein.
DR Bgee; ENSG00000065057; Expressed in right lobe of liver and 136 other tissues.
DR ExpressionAtlas; P78549; baseline and differential.
DR Genevisible; P78549; HS.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-UniRule.
DR GO; GO:0140078; F:class I DNA-(apurinic or apyrimidinic site) endonuclease activity; IDA:FlyBase.
DR GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
DR GO; GO:0019104; F:DNA N-glycosylase activity; IDA:UniProtKB.
DR GO; GO:0003906; F:DNA-(apurinic or apyrimidinic site) endonuclease activity; IDA:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0004519; F:endonuclease activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008534; F:oxidized purine nucleobase lesion DNA N-glycosylase activity; TAS:Reactome.
DR GO; GO:0000703; F:oxidized pyrimidine nucleobase lesion DNA N-glycosylase activity; IBA:GO_Central.
DR GO; GO:0006285; P:base-excision repair, AP site formation; IDA:UniProtKB.
DR GO; GO:0045008; P:depyrimidination; TAS:Reactome.
DR GO; GO:0006289; P:nucleotide-excision repair; IDA:UniProtKB.
DR GO; GO:0006296; P:nucleotide-excision repair, DNA incision, 5'-to lesion; IBA:GO_Central.
DR CDD; cd00056; ENDO3c; 1.
DR Gene3D; 1.10.1670.10; -; 1.
DR HAMAP; MF_03183; Endonuclease_III_Nth; 1.
DR InterPro; IPR011257; DNA_glycosylase.
DR InterPro; IPR004036; Endonuclease-III-like_CS2.
DR InterPro; IPR003651; Endonuclease3_FeS-loop_motif.
DR InterPro; IPR003265; HhH-GPD_domain.
DR InterPro; IPR023170; HhH_base_excis_C.
DR InterPro; IPR000445; HhH_motif.
DR InterPro; IPR030841; NTH1.
DR Pfam; PF00633; HHH; 1.
DR Pfam; PF00730; HhH-GPD; 1.
DR SMART; SM00478; ENDO3c; 1.
DR SMART; SM00525; FES; 1.
DR SUPFAM; SSF48150; SSF48150; 1.
DR PROSITE; PS01155; ENDONUCLEASE_III_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; 4Fe-4S; Alternative initiation; Direct protein sequencing;
KW DNA damage; DNA repair; Glycosidase; Hydrolase; Iron; Iron-sulfur; Lyase;
KW Metal-binding; Mitochondrion; Nucleus; Phosphoprotein; Reference proteome;
KW Transit peptide.
FT TRANSIT 1..30
FT /note="Mitochondrion"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183,
FT ECO:0000269|PubMed:12144783"
FT CHAIN 31..312
FT /note="Endonuclease III-like protein 1"
FT /id="PRO_0000102227"
FT DOMAIN 199..223
FT /note="HhH"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183"
FT REGION 1..79
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 36..60
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 1..17
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 34..52
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 62..79
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 220
FT /note="Nucleophile; for N-glycosylase activity"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183,
FT ECO:0000269|PubMed:9705289"
FT BINDING 290
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183"
FT BINDING 297
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183"
FT BINDING 300
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183"
FT BINDING 306
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03183"
FT SITE 239
FT /note="Important for catalytic activity"
FT MOD_RES 71
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 73
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT VAR_SEQ 1..15
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_054292"
FT VAR_SEQ 1..8
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9045706, ECO:0000303|PubMed:9705289,
FT ECO:0000303|PubMed:9831664"
FT /id="VSP_054293"
FT VARIANT 21
FT /note="R -> W (in dbSNP:rs3087469)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_016125"
FT VARIANT 33
FT /note="R -> K (in dbSNP:rs2302172)"
FT /id="VAR_016126"
FT VARIANT 176
FT /note="I -> T (in dbSNP:rs1805378)"
FT /id="VAR_016127"
FT VARIANT 234
FT /note="S -> L (in dbSNP:rs3211977)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_029318"
FT VARIANT 239
FT /note="D -> Y (in dbSNP:rs3087468)"
FT /id="VAR_016128"
FT MUTAGEN 40..42
FT /note="Missing: Sorted to the cytoplasm."
FT /evidence="ECO:0000269|PubMed:12531031"
FT MUTAGEN 42
FT /note="R->A: Sorted to both nuclei and mitochondria."
FT /evidence="ECO:0000269|PubMed:12531031"
FT MUTAGEN 42
FT /note="R->D: Sorted to the cytoplasm."
FT /evidence="ECO:0000269|PubMed:12531031"
FT MUTAGEN 57
FT /note="R->A,D: Sorted to both nuclei and mitochondria."
FT /evidence="ECO:0000269|PubMed:12531031"
FT MUTAGEN 220
FT /note="K->Q: Inactivates enzyme."
FT /evidence="ECO:0000269|PubMed:11695910,
FT ECO:0000269|PubMed:9705289"
FT MUTAGEN 220
FT /note="K->R: 85-fold reduction in activity. Uncouples the
FT glycosylase activity from the lyase activity. Shows
FT glycosylase activity without any detectable AP-lyase
FT activity during the first 10 min of the reaction."
FT /evidence="ECO:0000269|PubMed:11695910,
FT ECO:0000269|PubMed:9705289"
FT CONFLICT 9..10
FT /note="MT -> TS (in Ref. 8; CAA70865)"
FT /evidence="ECO:0000305"
FT CONFLICT 78
FT /note="Missing (in Ref. 8; CAA70865)"
FT /evidence="ECO:0000305"
FT CONFLICT 151
FT /note="M -> I (in Ref. 1; AAB41534)"
FT /evidence="ECO:0000305"
FT CONFLICT 160
FT /note="T -> A (in Ref. 1; AAB41534)"
FT /evidence="ECO:0000305"
FT HELIX 92..102
FT /evidence="ECO:0007829|PDB:7RDT"
FT TURN 103..105
FT /evidence="ECO:0007829|PDB:7RDS"
FT HELIX 109..114
FT /evidence="ECO:0007829|PDB:7RDS"
FT HELIX 125..138
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 144..157
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 161..165
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 169..176
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 182..199
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 208..211
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 219..230
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 240..248
FT /evidence="ECO:0007829|PDB:7RDT"
FT STRAND 252..254
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 259..267
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 272..274
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 277..288
FT /evidence="ECO:0007829|PDB:7RDT"
FT STRAND 292..294
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 297..299
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 303..305
FT /evidence="ECO:0007829|PDB:7RDT"
FT HELIX 307..310
FT /evidence="ECO:0007829|PDB:7RDT"
SQ SEQUENCE 312 AA; 34390 MW; 379816A1E0B45050 CRC64;
MCSPQESGMT ALSARMLTRS RSLGPGAGPR GCREEPGPLR RREAAAEARK SHSPVKRPRK
AQRLRVAYEG SDSEKGEGAE PLKVPVWEPQ DWQQQLVNIR AMRNKKDAPV DHLGTEHCYD
SSAPPKVRRY QVLLSLMLSS QTKDQVTAGA MQRLRARGLT VDSILQTDDA TLGKLIYPVG
FWRSKVKYIK QTSAILQQHY GGDIPASVAE LVALPGVGPK MAHLAMAVAW GTVSGIAVDT
HVHRIANRLR WTKKATKSPE ETRAALEEWL PRELWHEING LLVGFGQQTC LPVHPRCHAC
LNQALCPAAQ GL
