DNA2_HUMAN
ID DNA2_HUMAN Reviewed; 1060 AA.
AC P51530; Q2NKM1; Q5TC49; Q5TC50; Q6P455; Q6PI80; Q7Z6H9; Q8N346;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 12-DEC-2006, sequence version 3.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=DNA replication ATP-dependent helicase/nuclease DNA2;
DE Short=hDNA2;
DE AltName: Full=DNA replication ATP-dependent helicase-like homolog;
DE Includes:
DE RecName: Full=DNA replication nuclease DNA2;
DE EC=3.1.-.-;
DE Includes:
DE RecName: Full=DNA replication ATP-dependent helicase DNA2;
DE EC=3.6.4.12;
GN Name=DNA2; Synonyms=DNA2L, KIAA0083;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7788527; DOI=10.1093/dnares/2.1.37;
RA Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S.,
RA Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. III. The
RT coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:37-43(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 680-1060 (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 567-1060 (ISOFORM 1).
RC TISSUE=Colon, Duodenum, and Lymph;
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 [4]
RP FUNCTION.
RX PubMed=16595799; DOI=10.1093/nar/gkl102;
RA Kim J.H., Kim H.D., Ryu G.H., Kim D.H., Hurwitz J., Seo Y.S.;
RT "Isolation of human Dna2 endonuclease and characterization of its enzymatic
RT properties.";
RL Nucleic Acids Res. 34:1854-1864(2006).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-277 AND LYS-654.
RX PubMed=16595800; DOI=10.1093/nar/gkl070;
RA Masuda-Sasa T., Imamura O., Campbell J.L.;
RT "Biochemical analysis of human Dna2.";
RL Nucleic Acids Res. 34:1865-1875(2006).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18995831; DOI=10.1016/j.molcel.2008.09.024;
RA Zheng L., Zhou M., Guo Z., Lu H., Qian L., Dai H., Qiu J., Yakubovskaya E.,
RA Bogenhagen D.F., Demple B., Shen B.;
RT "Human DNA2 is a mitochondrial nuclease/helicase for efficient processing
RT of DNA replication and repair intermediates.";
RL Mol. Cell 32:325-336(2008).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19487465; DOI=10.1128/mcb.01834-08;
RA Duxin J.P., Dao B., Martinsson P., Rajala N., Guittat L., Campbell J.L.,
RA Spelbrink J.N., Stewart S.A.;
RT "Human Dna2 is a nuclear and mitochondrial DNA maintenance protein.";
RL Mol. Cell. Biol. 29:4274-4282(2009).
RN [8]
RP ACETYLATION.
RX PubMed=20019387; DOI=10.1074/jbc.m109.086397;
RA Balakrishnan L., Stewart J., Polaczek P., Campbell J.L., Bambara R.A.;
RT "Acetylation of Dna2 endonuclease/helicase and flap endonuclease 1 by p300
RT promotes DNA stability by creating long flap intermediates.";
RL J. Biol. Chem. 285:4398-4404(2010).
RN [9]
RP FUNCTION, INTERACTION WITH BLM, AND MUTAGENESIS OF ASP-277 AND LYS-654.
RX PubMed=21325134; DOI=10.1101/gad.2003811;
RA Nimonkar A.V., Genschel J., Kinoshita E., Polaczek P., Campbell J.L.,
RA Wyman C., Modrich P., Kowalczykowski S.C.;
RT "BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection
RT machineries for human DNA break repair.";
RL Genes Dev. 25:350-362(2011).
RN [10]
RP FUNCTION, DNA-BINDING, AND MUTAGENESIS OF LYS-654.
RX PubMed=21572043; DOI=10.1074/jbc.m111.243071;
RA Fortini B.K., Pokharel S., Polaczek P., Balakrishnan L., Bambara R.A.,
RA Campbell J.L.;
RT "Characterization of the endonuclease and ATP-dependent flap
RT endo/exonuclease of Dna2.";
RL J. Biol. Chem. 286:23763-23770(2011).
RN [11]
RP FUNCTION, DNA-BINDING, INTERACTION WITH WDHD1, AND MUTAGENESIS OF ASP-277
RP AND LYS-654.
RX PubMed=22570476; DOI=10.1074/jbc.m112.359018;
RA Duxin J.P., Moore H.R., Sidorova J., Karanja K., Honaker Y., Dao B.,
RA Piwnica-Worms H., Campbell J.L., Monnat R.J. Jr., Stewart S.A.;
RT "Okazaki fragment processing-independent role for human Dna2 enzyme during
RT DNA replication.";
RL J. Biol. Chem. 287:21980-21991(2012).
RN [12]
RP FUNCTION, AND DNA-BINDING.
RX PubMed=22570407; DOI=10.1093/nar/gks388;
RA Gloor J.W., Balakrishnan L., Campbell J.L., Bambara R.A.;
RT "Biochemical analyses indicate that binding and cleavage specificities
RT define the ordered processing of human Okazaki fragments by Dna2 and
RT FEN1.";
RL Nucleic Acids Res. 40:6774-6786(2012).
RN [13]
RP INVOLVEMENT IN SCKL8.
RX PubMed=24389050; DOI=10.1101/gr.160572.113;
RA Shaheen R., Faqeih E., Ansari S., Abdel-Salam G., Al-Hassnan Z.N.,
RA Al-Shidi T., Alomar R., Sogaty S., Alkuraya F.S.;
RT "Genomic analysis of primordial dwarfism reveals novel disease genes.";
RL Genome Res. 24:291-299(2014).
RN [14]
RP VARIANTS PEOA6 HIS-198; GLU-227 AND ILE-637, AND CHARACTERIZATION OF
RP VARIANTS PEOA6 HHIS-198; GLU-227 AND ILE-637.
RX PubMed=23352259; DOI=10.1016/j.ajhg.2012.12.014;
RA Ronchi D., Di Fonzo A., Lin W., Bordoni A., Liu C., Fassone E.,
RA Pagliarani S., Rizzuti M., Zheng L., Filosto M., Ferro M.T., Ranieri M.,
RA Magri F., Peverelli L., Li H., Yuan Y.C., Corti S., Sciacco M., Moggio M.,
RA Bresolin N., Shen B., Comi G.P.;
RT "Mutations in DNA2 link progressive myopathy to mitochondrial DNA
RT instability.";
RL Am. J. Hum. Genet. 92:293-300(2013).
CC -!- FUNCTION: Key enzyme involved in DNA replication and DNA repair in
CC nucleus and mitochondrion. Involved in Okazaki fragments processing by
CC cleaving long flaps that escape FEN1: flaps that are longer than 27
CC nucleotides are coated by replication protein A complex (RPA), leading
CC to recruit DNA2 which cleaves the flap until it is too short to bind
CC RPA and becomes a substrate for FEN1. Also involved in 5'-end resection
CC of DNA during double-strand break (DSB) repair: recruited by BLM and
CC mediates the cleavage of 5'-ssDNA, while the 3'-ssDNA cleavage is
CC prevented by the presence of RPA. Also involved in DNA replication
CC checkpoint independently of Okazaki fragments processing. Possesses
CC different enzymatic activities, such as single-stranded DNA (ssDNA)-
CC dependent ATPase, 5'-3' helicase and endonuclease activities. While the
CC ATPase and endonuclease activities are well-defined and play a key role
CC in Okazaki fragments processing and DSB repair, the 5'-3' DNA helicase
CC activity is subject to debate. According to various reports, the
CC helicase activity is weak and its function remains largely unclear.
CC Helicase activity may promote the motion of DNA2 on the flap, helping
CC the nuclease function. {ECO:0000269|PubMed:16595799,
CC ECO:0000269|PubMed:16595800, ECO:0000269|PubMed:18995831,
CC ECO:0000269|PubMed:19487465, ECO:0000269|PubMed:21325134,
CC ECO:0000269|PubMed:21572043, ECO:0000269|PubMed:22570407,
CC ECO:0000269|PubMed:22570476}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12;
CC Evidence={ECO:0000269|PubMed:16595800};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; Evidence={ECO:0000250};
CC Note=Binds 1 [4Fe-4S] cluster. {ECO:0000250};
CC -!- SUBUNIT: Interacts with BLM and WDHD1. {ECO:0000269|PubMed:21325134,
CC ECO:0000269|PubMed:22570476}.
CC -!- SUBCELLULAR LOCATION: Nucleus. Mitochondrion. Note=Was initially
CC reported to be exclusively mitochondrial (PubMed:18995831). However, it
CC was later shown to localize both in mitochondrion and nucleus
CC (PubMed:19487465). {ECO:0000269|PubMed:18995831,
CC ECO:0000269|PubMed:19487465}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P51530-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P51530-2; Sequence=VSP_021870, VSP_021871;
CC Name=3;
CC IsoId=P51530-3; Sequence=VSP_021869;
CC Name=4;
CC IsoId=P51530-4; Sequence=VSP_044185;
CC -!- PTM: Acetylated by EP300, leading to stimulate the 5'-3' endonuclease,
CC the 5'-3' helicase and DNA-dependent ATPase activities, possibly by
CC increasing DNA substrate affinity. {ECO:0000269|PubMed:20019387}.
CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA
CC deletions, autosomal dominant, 6 (PEOA6) [MIM:615156]: A disorder
CC characterized by muscle weakness, mainly affecting the lower limbs,
CC external ophthalmoplegia, exercise intolerance, and mitochondrial DNA
CC deletions on muscle biopsy. Symptoms may appear in childhood or
CC adulthood and show slow progression. {ECO:0000269|PubMed:23352259}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Seckel syndrome 8 (SCKL8) [MIM:615807]: A rare autosomal
CC recessive disorder characterized by proportionate dwarfism of prenatal
CC onset associated with low birth weight, growth retardation, severe
CC microcephaly with a bird-headed like appearance, and intellectual
CC disability. {ECO:0000269|PubMed:24389050}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the DNA2/NAM7 helicase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH28188.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH63664.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA07647.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; D42046; BAA07647.1; ALT_INIT; mRNA.
DR EMBL; AL136233; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC041115; AAH41115.1; -; mRNA.
DR EMBL; BC053574; AAH53574.1; -; mRNA.
DR EMBL; BC063664; AAH63664.1; ALT_INIT; mRNA.
DR EMBL; BC111740; AAI11741.1; -; mRNA.
DR EMBL; BC028188; AAH28188.1; ALT_INIT; mRNA.
DR CCDS; CCDS44415.2; -. [P51530-1]
DR PIR; T50697; T50697.
DR RefSeq; NP_001073918.2; NM_001080449.2. [P51530-1]
DR PDB; 5EAY; X-ray; 1.55 A; E/F/G/H=5-17.
DR PDBsum; 5EAY; -.
DR AlphaFoldDB; P51530; -.
DR SMR; P51530; -.
DR BioGRID; 108103; 75.
DR IntAct; P51530; 22.
DR STRING; 9606.ENSP00000351185; -.
DR ChEMBL; CHEMBL4523236; -.
DR iPTMnet; P51530; -.
DR PhosphoSitePlus; P51530; -.
DR BioMuta; DNA2; -.
DR EPD; P51530; -.
DR jPOST; P51530; -.
DR MassIVE; P51530; -.
DR MaxQB; P51530; -.
DR PaxDb; P51530; -.
DR PeptideAtlas; P51530; -.
DR PRIDE; P51530; -.
DR ProteomicsDB; 56322; -. [P51530-1]
DR ProteomicsDB; 56323; -. [P51530-2]
DR ProteomicsDB; 56324; -. [P51530-3]
DR Antibodypedia; 28503; 153 antibodies from 26 providers.
DR DNASU; 1763; -.
DR Ensembl; ENST00000358410.8; ENSP00000351185.3; ENSG00000138346.15. [P51530-1]
DR Ensembl; ENST00000399179.6; ENSP00000382132.3; ENSG00000138346.15. [P51530-2]
DR Ensembl; ENST00000399180.3; ENSP00000382133.3; ENSG00000138346.15. [P51530-2]
DR GeneID; 1763; -.
DR KEGG; hsa:1763; -.
DR MANE-Select; ENST00000358410.8; ENSP00000351185.3; NM_001080449.3; NP_001073918.2.
DR UCSC; uc057tqx.1; human. [P51530-1]
DR CTD; 1763; -.
DR DisGeNET; 1763; -.
DR GeneCards; DNA2; -.
DR HGNC; HGNC:2939; DNA2.
DR HPA; ENSG00000138346; Tissue enhanced (lymphoid).
DR MalaCards; DNA2; -.
DR MIM; 601810; gene.
DR MIM; 615156; phenotype.
DR MIM; 615807; phenotype.
DR neXtProt; NX_P51530; -.
DR OpenTargets; ENSG00000138346; -.
DR Orphanet; 352470; DNA2-related mitochondrial DNA deletion syndrome.
DR VEuPathDB; HostDB:ENSG00000138346; -.
DR eggNOG; KOG1805; Eukaryota.
DR GeneTree; ENSGT00780000122010; -.
DR HOGENOM; CLU_001666_2_0_1; -.
DR InParanoid; P51530; -.
DR OMA; NYCEAAI; -.
DR OrthoDB; 633768at2759; -.
DR PhylomeDB; P51530; -.
DR PathwayCommons; P51530; -.
DR Reactome; R-HSA-174437; Removal of the Flap Intermediate from the C-strand.
DR Reactome; R-HSA-5685938; HDR through Single Strand Annealing (SSA).
DR Reactome; R-HSA-5685942; HDR through Homologous Recombination (HRR).
DR Reactome; R-HSA-5693554; Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA).
DR Reactome; R-HSA-5693568; Resolution of D-loop Structures through Holliday Junction Intermediates.
DR Reactome; R-HSA-5693579; Homologous DNA Pairing and Strand Exchange.
DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-HSA-5693616; Presynaptic phase of homologous DNA pairing and strand exchange.
DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-HSA-69166; Removal of the Flap Intermediate.
DR Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR Reactome; R-HSA-9701192; Defective HDR through Homologous Recombination (HRR) due to BRCA1 loss-of-function.
DR Reactome; R-HSA-9704331; Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function.
DR Reactome; R-HSA-9704646; Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function.
DR Reactome; R-HSA-9709570; Impaired BRCA2 binding to RAD51.
DR Reactome; R-HSA-9709603; Impaired BRCA2 binding to PALB2.
DR SignaLink; P51530; -.
DR BioGRID-ORCS; 1763; 40 hits in 232 CRISPR screens.
DR ChiTaRS; DNA2; human.
DR GeneWiki; DNA2L; -.
DR GenomeRNAi; 1763; -.
DR Pharos; P51530; Tbio.
DR PRO; PR:P51530; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P51530; protein.
DR Bgee; ENSG00000138346; Expressed in secondary oocyte and 115 other tissues.
DR ExpressionAtlas; P51530; baseline and differential.
DR Genevisible; P51530; HS.
DR GO; GO:0000781; C:chromosome, telomeric region; ISS:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-KW.
DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB.
DR GO; GO:0017108; F:5'-flap endonuclease activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; TAS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003678; F:DNA helicase activity; IDA:UniProtKB.
DR GO; GO:0004386; F:helicase activity; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004518; F:nuclease activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IBA:GO_Central.
DR GO; GO:0017116; F:single-stranded DNA helicase activity; IDA:UniProtKB.
DR GO; GO:0016890; F:site-specific endodeoxyribonuclease activity, specific for altered base; IDA:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; IDA:UniProtKB.
DR GO; GO:0000729; P:DNA double-strand break processing; IDA:UniProtKB.
DR GO; GO:0006260; P:DNA replication; IMP:UniProtKB.
DR GO; GO:0000076; P:DNA replication checkpoint signaling; IMP:UniProtKB.
DR GO; GO:0033567; P:DNA replication, Okazaki fragment processing; IDA:UniProtKB.
DR GO; GO:0043137; P:DNA replication, removal of RNA primer; IDA:UniProtKB.
DR GO; GO:0044806; P:G-quadruplex DNA unwinding; TAS:BHF-UCL.
DR GO; GO:0043504; P:mitochondrial DNA repair; IDA:UniProtKB.
DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:UniProtKB.
DR GO; GO:1902990; P:mitotic telomere maintenance via semi-conservative replication; ISS:BHF-UCL.
DR GO; GO:0090305; P:nucleic acid phosphodiester bond hydrolysis; ISS:BHF-UCL.
DR GO; GO:0045740; P:positive regulation of DNA replication; IDA:UniProtKB.
DR GO; GO:0071932; P:replication fork reversal; IBA:GO_Central.
DR GO; GO:0090656; P:t-circle formation; TAS:BHF-UCL.
DR GO; GO:0000723; P:telomere maintenance; ISS:BHF-UCL.
DR GO; GO:0032201; P:telomere maintenance via semi-conservative replication; TAS:Reactome.
DR CDD; cd18808; SF1_C_Upf1; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR Gene3D; 3.90.320.10; -; 1.
DR InterPro; IPR026851; Dna2.
DR InterPro; IPR045055; DNA2/NAM7-like.
DR InterPro; IPR041679; DNA2/NAM7-like_C.
DR InterPro; IPR041677; DNA2/NAM7_AAA_11.
DR InterPro; IPR014808; DNA_replication_fac_Dna2_N.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR011604; PDDEXK-like_dom_sf.
DR PANTHER; PTHR10887; PTHR10887; 1.
DR PANTHER; PTHR10887:SF433; PTHR10887:SF433; 1.
DR Pfam; PF13086; AAA_11; 2.
DR Pfam; PF13087; AAA_12; 1.
DR Pfam; PF08696; Dna2; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
PE 1: Evidence at protein level;
KW 3D-structure; 4Fe-4S; Acetylation; Alternative splicing; ATP-binding;
KW Disease variant; DNA damage; DNA repair; DNA replication; DNA-binding;
KW Dwarfism; Endonuclease; Helicase; Hydrolase; Intellectual disability; Iron;
KW Iron-sulfur; Metal-binding; Mitochondrion; Multifunctional enzyme;
KW Nuclease; Nucleotide-binding; Nucleus; Primary mitochondrial disease;
KW Progressive external ophthalmoplegia; Reference proteome.
FT CHAIN 1..1060
FT /note="DNA replication ATP-dependent helicase/nuclease
FT DNA2"
FT /id="PRO_0000080712"
FT REGION 81..519
FT /note="Nuclease activity"
FT /evidence="ECO:0000250"
FT REGION 520..1060
FT /note="Helicase activity"
FT /evidence="ECO:0000250"
FT BINDING 136
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000250"
FT BINDING 393
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000250"
FT BINDING 396
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000250"
FT BINDING 402
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000250"
FT BINDING 648..655
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255"
FT VAR_SEQ 663..900
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_021869"
FT VAR_SEQ 664..687
FT /note="ILYACGFSVLLTSYTHSAVDNILL -> FRRFIQLSSNLQSKKFADQSPLNP
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_021870"
FT VAR_SEQ 688..1060
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_021871"
FT VAR_SEQ 1040..1060
FT /note="IDLPSREHESLCHILGDFQRE -> SFFFCIWSHLIAL (in isoform
FT 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044185"
FT VARIANT 198
FT /note="R -> H (in PEOA6; the mutant protein has a complete
FT loss of nuclease activity and severely impaired helicase
FT activity; consistent with a loss of function mutation;
FT dbSNP:rs1272393477)"
FT /evidence="ECO:0000269|PubMed:23352259"
FT /id="VAR_069905"
FT VARIANT 227
FT /note="K -> E (in PEOA6; the mutant protein has
FT significantly reduced nuclease and helicase activity;
FT consistent with a loss of function mutation;
FT dbSNP:rs760412883)"
FT /evidence="ECO:0000269|PubMed:23352259"
FT /id="VAR_069906"
FT VARIANT 637
FT /note="V -> I (in PEOA6; the mutant protein has decreased
FT nuclease activity (30% of wild-type) and enhanced helicase
FT activity; consistent with a loss of function mutation;
FT dbSNP:rs746522359)"
FT /evidence="ECO:0000269|PubMed:23352259"
FT /id="VAR_069907"
FT MUTAGEN 277
FT /note="D->A: Abolishes ability to resect DNA in present of
FT BLM."
FT /evidence="ECO:0000269|PubMed:16595800,
FT ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:22570476"
FT MUTAGEN 654
FT /note="K->E: Abolishes ability to unwind DNA, while it does
FT not affect ability to resect DNA."
FT /evidence="ECO:0000269|PubMed:16595800,
FT ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:21572043,
FT ECO:0000269|PubMed:22570476"
FT CONFLICT 986
FT /note="K -> N (in Ref. 3; AAH28188)"
FT /evidence="ECO:0000305"
FT HELIX 7..10
FT /evidence="ECO:0007829|PDB:5EAY"
SQ SEQUENCE 1060 AA; 120415 MW; 727D4B268FD75C5A CRC64;
MEQLNELELL MEKSFWEEAE LPAELFQKKV VASFPRTVLS TGMDNRYLVL AVNTVQNKEG
NCEKRLVITA SQSLENKELC ILRNDWCSVP VEPGDIIHLE GDCTSDTWII DKDFGYLILY
PDMLISGTSI ASSIRCMRRA VLSETFRSSD PATRQMLIGT VLHEVFQKAI NNSFAPEKLQ
ELAFQTIQEI RHLKEMYRLN LSQDEIKQEV EDYLPSFCKW AGDFMHKNTS TDFPQMQLSL
PSDNSKDNST CNIEVVKPMD IEESIWSPRF GLKGKIDVTV GVKIHRGYKT KYKIMPLELK
TGKESNSIEH RSQVVLYTLL SQERRADPEA GLLLYLKTGQ MYPVPANHLD KRELLKLRNQ
MAFSLFHRIS KSATRQKTQL ASLPQIIEEE KTCKYCSQIG NCALYSRAVE QQMDCSSVPI
VMLPKIEEET QHLKQTHLEY FSLWCLMLTL ESQSKDNKKN HQNIWLMPAS EMEKSGSCIG
NLIRMEHVKI VCDGQYLHNF QCKHGAIPVT NLMAGDRVIV SGEERSLFAL SRGYVKEINM
TTVTCLLDRN LSVLPESTLF RLDQEEKNCD IDTPLGNLSK LMENTFVSKK LRDLIIDFRE
PQFISYLSSV LPHDAKDTVA CILKGLNKPQ RQAMKKVLLS KDYTLIVGMP GTGKTTTICT
LVRILYACGF SVLLTSYTHS AVDNILLKLA KFKIGFLRLG QIQKVHPAIQ QFTEQEICRS
KSIKSLALLE ELYNSQLIVA TTCMGINHPI FSRKIFDFCI VDEASQISQP ICLGPLFFSR
RFVLVGDHQQ LPPLVLNREA RALGMSESLF KRLEQNKSAV VQLTVQYRMN SKIMSLSNKL
TYEGKLECGS DKVANAVINL RHFKDVKLEL EFYADYSDNP WLMGVFEPNN PVCFLNTDKV
PAPEQVEKGG VSNVTEAKLI VFLTSIFVKA GCSPSDIGII APYRQQLKII NDLLARSIGM
VEVNTVDKYQ GRDKSIVLVS FVRSNKDGTV GELLKDWRRL NVAITRAKHK LILLGCVPSL
NCYPPLEKLL NHLNSEKLII DLPSREHESL CHILGDFQRE
