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 04-NOV-2026, entry version 193. 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=5.6.2.3 {ECO:0000269|PubMed:16595800, ECO:0000269|PubMed:20019387}; DE AltName: Full=DNA 5'-3' helicase DNA2 {ECO:0000305}; 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 CATALYTIC ACTIVITY, AND 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 INVOLVEMENT IN RTS4, AND VARIANT RTS4 PRO-48. RX PubMed=37055165; DOI=10.1136/jmg-2022-109119; RA Di Lazzaro Filho R., Yamamoto G.L., Silva T.J., Rocha L.A., RA Linnenkamp B.D.W., Castro M.A.A., Bartholdi D., Schaller A., Leeb T., RA Kelmann S., Utagawa C.Y., Steiner C.E., Steinmetz L., Honjo R.S., Kim C.A., RA Wang L., Abourjaili-Bilodeau R., Campeau P.M., Warman M., RA Passos-Bueno M.R., Hoch N.C., Bertola D.R.; RT "Biallelic variants in DNA2 cause poikiloderma with congenital cataracts RT and severe growth failure reminiscent of Rothmund-Thomson syndrome."; RL J. Med. Genet. 60:1127-1132(2023). RN [15] 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). RN [16] RP VARIANTS PEOA6 GLY-221; LEU-552; LEU-640 AND HIS-956, CHARACTERIZATION OF RP VARIANTS PEOA6 GLY-221; LEU-552; LEU-640 AND HIS-956, AND FUNCTION. RX PubMed=31478350; DOI=10.1002/acn3.50888; RA Ronchi D., Liu C., Caporali L., Piga D., Li H., Tagliavini F., RA Valentino M.L., Ferro M.T., Bini P., Zheng L., Carelli V., Shen B., RA Comi G.P.; RT "Novel mutations in DNA2 associated with myopathy and mtDNA instability."; RL Ann. Clin. Transl. Neurol. 6:1893-1899(2019). RN [17] RP VARIANT SCKL8 ALA-655. RX PubMed=31045292; DOI=10.1002/humu.23776; RA Tarnauskaite Z., Bicknell L.S., Marsh J.A., Murray J.E., Parry D.A., RA Logan C.V., Bober M.B., de Silva D.C., Duker A.L., Sillence D., Wise C., RA Jackson A.P., Murina O., Reijns M.A.M.; RT "Biallelic variants in DNA2 cause microcephalic primordial dwarfism."; RL Hum. Mutat. 40:1063-1070(2019). 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 absent to weak and its function remains largely CC unclear. Helicase activity may promote the motion of DNA2 on the flap, CC helping 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, ECO:0000269|PubMed:31478350}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the CC replication fork by translocating in the 5'-3' direction.; CC EC=5.6.2.3; Evidence={ECO:0000269|PubMed:16595800, CC ECO:0000269|PubMed:20019387}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3; CC Evidence={ECO:0000269|PubMed:16595800, ECO:0000269|PubMed:20019387}; CC -!- COFACTOR: CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; CC Evidence={ECO:0000250|UniProtKB:P38859}; CC Note=Binds 1 [4Fe-4S] cluster. {ECO:0000250|UniProtKB:P38859}; 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 stimulation of the 5'-3' CC endonuclease, and small increases in the weak 5'-3' helicase and DNA- CC dependent ATPase activities, possibly by increasing DNA substrate CC 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 ECO:0000269|PubMed:31478350}. Note=The disease is caused by variants CC affecting the gene represented 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, ECO:0000269|PubMed:31045292}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Rothmund-Thomson syndrome 4 (RTS4) [MIM:620819]: A form of CC Rothmund-Thomson syndrome, a disorder characterized by sparse hair, CC eyebrows and eyelashes, juvenile cataracts, and poikiloderma, a CC genodermatosis presenting with mottled pigmentation, telangiectasia and CC epidermal atrophy. Additional features are short stature, dysplastic CC nails, and skeletal and dental abnormalities. Inheritance is autosomal CC recessive. RTS4 patients also exhibit microcephaly and photosensitivity CC with bullae. Growth failure is severe, with some individuals showing CC signs of growth hormone or combined pituitary hormone deficiency. CC {ECO:0000269|PubMed:37055165}. Note=The disease is caused by variants CC 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_001080449.3. [P51530-1] DR PDB; 5EAY; X-ray; 1.55 A; E/F/G/H=5-17. DR AlphaFoldDB; P51530; -. DR SMR; P51530; -. DR BioGRID; 108103; 90. DR FunCoup; P51530; 2761. DR IntAct; P51530; 52. DR STRING; 9606.ENSP00000351185; -. DR ChEMBL; CHEMBL4523236; -. DR GlyGen; P51530; 1 site, 1 N-linked glycan (1 site). DR iPTMnet; P51530; -. DR PhosphoSitePlus; P51530; -. DR BioMuta; DNA2; -. DR jPOST; P51530; -. DR MassIVE; P51530; -. DR PaxDb; 9606-ENSP00000351185; -. DR PeptideAtlas; P51530; -. DR ProteomicsDB; 56322; -. [P51530-1] DR ProteomicsDB; 56323; -. [P51530-2] DR ProteomicsDB; 56324; -. [P51530-3] DR Pumba; P51530; -. DR Antibodypedia; 28503; 173 antibodies from 28 providers. DR DNASU; 1763; -. DR Ensembl; ENST00000358410.8; ENSP00000351185.3; ENSG00000138346.17. [P51530-1] DR Ensembl; ENST00000399179.6; ENSP00000382132.3; ENSG00000138346.17. [P51530-2] DR Ensembl; ENST00000936801.1; ENSP00000606860.1; ENSG00000138346.17. [P51530-3] 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 AGR; HGNC:2939; -. 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 MIM; 620819; phenotype. DR OpenTargets; ENSG00000138346; -. DR Orphanet; 352470; DNA2-related mitochondrial DNA deletion syndrome. DR Orphanet; 715635; Rothmund-Thomson syndrome type 4. DR Orphanet; 808; Seckel syndrome. DR VEuPathDB; HostDB:ENSG00000138346; -. DR eggNOG; KOG1805; Eukaryota. DR GeneTree; ENSGT00780000122010; -. DR HOGENOM; CLU_001666_2_0_1; -. DR InParanoid; P51530; -. DR OMA; AACDNCY; -. DR OrthoDB; 306218at2759; -. DR PAN-GO; P51530; 4 GO annotations based on evolutionary models. 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 homologous recombination repair (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 SIGNOR; P51530; -. DR Agora; ENSG00000138346; -. DR BioGRID-ORCS; 1763; 67 hits in 295 CRISPR screens. DR ChiTaRS; DNA2; human. DR EvolutionaryTrace; P51530; -. 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 116 other cell types or tissues. DR ExpressionAtlas; P51530; baseline and differential. 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; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. 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:0016887; F:ATP hydrolysis activity; IMP:UniProtKB. DR GO; GO:0033892; F:deoxyribonuclease (pyrimidine dimer) activity; IDA: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: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:0006284; P:base-excision repair; IDA:UniProtKB. DR GO; GO:0000729; P:DNA double-strand break processing; IDA:UniProtKB. DR GO; GO:0032392; P:DNA geometric change; TAS:BHF-UCL. 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: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: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; cd18041; DEXXQc_DNA2; 1. DR CDD; cd22318; DNA2_N-like; 1. DR CDD; cd18808; SF1_C_Upf1; 1. DR FunFam; 3.40.50.300:FF:000721; DNA replication ATP-dependent helicase/nuclease DNA2; 1. DR FunFam; 3.40.50.300:FF:000789; DNA replication ATP-dependent helicase/nuclease DNA2; 1. DR FunFam; 3.40.50.300:FF:000915; DNA replication ATP-dependent helicase/nuclease DNA2; 1. DR FunFam; 3.90.320.10:FF:000002; DNA replication ATP-dependent helicase/nuclease DNA2; 1. DR Gene3D; 3.90.320.10; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR InterPro; IPR026851; Dna2/JHS1_DEXXQ-box. DR InterPro; IPR041679; DNA2/NAM7-like_C. DR InterPro; IPR041677; DNA2/NAM7_AAA_11. DR InterPro; IPR048459; DNA2_Rift. DR InterPro; IPR014808; DNA_replication_fac_Dna2_N. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR011604; PDDEXK-like_dom_sf. DR InterPro; IPR047187; SF1_C_Upf1. DR PANTHER; PTHR36531; CRISPR-ASSOCIATED EXONUCLEASE CAS4; 1. DR PANTHER; PTHR36531:SF6; DNA REPLICATION ATP-DEPENDENT HELICASE_NUCLEASE DNA2; 1. DR Pfam; PF13086; AAA_11; 2. DR Pfam; PF13087; AAA_12; 1. DR Pfam; PF08696; Dna2; 1. DR Pfam; PF21123; Dna2_Rift; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS52088; UPF1_HELICASE; 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; Ectodermal dysplasia; Endonuclease; Helicase; Hydrolase; KW Hypotrichosis; Intellectual disability; Iron; Iron-sulfur; Isomerase; KW Metal-binding; Mitochondrion; Multifunctional enzyme; Nuclease; KW Nucleotide-binding; Nucleus; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome. FT CHAIN 1..1060 FT /note="DNA replication ATP-dependent helicase/nuclease FT DNA2" FT /id="PRO_0000080712" FT DOMAIN 625..823 FT /note="UPF1-type SF1B helicase ATP-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01433" FT DOMAIN 824..1052 FT /note="UPF1-type SF1B helicase C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01433" 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 651..656 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01433" 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 48 FT /note="L -> P (in RTS4; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:37055165" FT /id="VAR_089691" FT VARIANT 198 FT /note="R -> H (in PEOA6; uncertain significance; the mutant FT protein has a complete loss of nuclease activity and FT severely impaired helicase activity; dbSNP:rs1272393477)" FT /evidence="ECO:0000269|PubMed:23352259" FT /id="VAR_069905" FT VARIANT 221 FT /note="A -> G (in PEOA6; uncertain significance; modestly FT decreased of both ATP hydrolysis activity and nuclease FT activity; dbSNP:rs751031650)" FT /evidence="ECO:0000269|PubMed:31478350" FT /id="VAR_089692" FT VARIANT 227 FT /note="K -> E (in PEOA6; uncertain significance; the mutant FT protein has significantly reduced nuclease and helicase FT activity; consistent with a loss of function mutation; FT dbSNP:rs760412883)" FT /evidence="ECO:0000269|PubMed:23352259" FT /id="VAR_069906" FT VARIANT 552 FT /note="S -> L (in PEOA6; uncertain significance; decreased FT both ATP hydrolysis activity and nuclease activity; FT dbSNP:rs910368080)" FT /evidence="ECO:0000269|PubMed:31478350" FT /id="VAR_089693" FT VARIANT 637 FT /note="V -> I (in PEOA6; uncertain significance; the mutant FT protein has decreased nuclease activity (30% of wild-type) FT and enhanced helicase activity; consistent with a loss of FT function mutation; dbSNP:rs746522359)" FT /evidence="ECO:0000269|PubMed:23352259" FT /id="VAR_069907" FT VARIANT 640 FT /note="S -> L (in PEOA6; likely pathogenic; abolished both FT ATP hydrolysis activity and nuclease activity; FT dbSNP:rs1590054876)" FT /evidence="ECO:0000269|PubMed:31478350" FT /id="VAR_089694" FT VARIANT 655 FT /note="T -> A (in SCKL8; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:31045292" FT /id="VAR_089695" FT VARIANT 956 FT /note="R -> H (in PEOA6; uncertain significance; no effect FT on both ATP hydrolysis activity and nuclease activity; FT dbSNP:rs747301191)" FT /evidence="ECO:0000269|PubMed:31478350" FT /id="VAR_089696" 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 //