ID EXD2_HUMAN Reviewed; 621 AA. AC Q9NVH0; B4DIH6; G5E947; Q6AWB6; Q8N3D3; DT 24-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 31-OCT-2012, sequence version 2. DT 27-MAR-2024, entry version 173. DE RecName: Full=Exonuclease 3'-5' domain-containing protein 2 {ECO:0000303|PubMed:26807646}; DE EC=3.1.11.1 {ECO:0000269|PubMed:26807646, ECO:0000269|PubMed:31127291}; DE AltName: Full=3'-5' exoribonuclease EXD2 {ECO:0000305}; DE EC=3.1.13.- {ECO:0000269|PubMed:29335528, ECO:0000269|PubMed:31127291}; DE AltName: Full=Exonuclease 3'-5' domain-like-containing protein 2 {ECO:0000303|PubMed:26807646}; GN Name=EXD2 {ECO:0000303|PubMed:26807646, ECO:0000312|HGNC:HGNC:20217}; GN Synonyms=C14orf114 {ECO:0000312|HGNC:HGNC:20217}, EXDL2 GN {ECO:0000303|PubMed:26807646}; 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] (ISOFORMS 1 AND 2), AND VARIANT RP HIS-518. RC TISSUE=Hippocampus, and Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP HIS-518. RC TISSUE=Endometrium, and Melanoma; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 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 [6] RP FUNCTION. RX PubMed=20603073; DOI=10.1016/j.molcel.2010.06.023; RA Smogorzewska A., Desetty R., Saito T.T., Schlabach M., Lach F.P., RA Sowa M.E., Clark A.B., Kunkel T.A., Harper J.W., Colaiacovo M.P., RA Elledge S.J.; RT "A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease RT necessary for DNA interstrand crosslink repair."; RL Mol. Cell 39:36-47(2010). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP 108-ASP--GLU-110, AND INTERACTION WITH BRCA1; MRE11 AND RBBP8. RX PubMed=26807646; DOI=10.1038/ncb3303; RA Broderick R., Nieminuszczy J., Baddock H.T., Deshpande R.A., Gileadi O., RA Paull T.T., McHugh P.J., Niedzwiedz W.; RT "EXD2 promotes homologous recombination by facilitating DNA end RT resection."; RL Nat. Cell Biol. 18:271-280(2016). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=29335528; DOI=10.1038/s41556-017-0016-9; RA Silva J., Aivio S., Knobel P.A., Bailey L.J., Casali A., Vinaixa M., RA Garcia-Cao I., Coyaud E., Jourdain A.A., Perez-Ferreros P., Rojas A.M., RA Antolin-Fontes A., Samino-Gene S., Raught B., Gonzalez-Reyes A., RA Ribas de Pouplana L., Doherty A.J., Yanes O., Stracker T.H.; RT "EXD2 governs germ stem cell homeostasis and lifespan by promoting RT mitoribosome integrity and translation."; RL Nat. Cell Biol. 20:162-174(2018). RN [10] RP SUBCELLULAR LOCATION. RX PubMed=29599527; DOI=10.1038/s41598-018-23690-y; RA Hensen F., Moretton A., van Esveld S., Farge G., Spelbrink J.N.; RT "The mitochondrial outer-membrane location of the EXD2 exonuclease RT contradicts its direct role in nuclear DNA repair."; RL Sci. Rep. 8:5368-5368(2018). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 108-ASP--GLU-110. RX PubMed=31255466; DOI=10.1016/j.molcel.2019.05.026; RA Nieminuszczy J., Broderick R., Bellani M.A., Smethurst E., Schwab R.A., RA Cherdyntseva V., Evmorfopoulou T., Lin Y.L., Minczuk M., Pasero P., RA Gagos S., Seidman M.M., Niedzwiedz W.; RT "EXD2 protects stressed replication forks and is required for cell RT viability in the absence of BRCA1/2."; RL Mol. Cell 0:0-0(2019). RN [12] {ECO:0007744|PDB:6K1E} RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 76-295 IN COMPLEX WITH MAGNESIUM RP AND MANGANESE, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, SUBCELLULAR RP LOCATION, TOPOLOGY, AND MUTAGENESIS OF ARG-190; ARG-195; ARG-197; LYS-221 RP AND ARG-226. RX PubMed=31127291; DOI=10.1093/nar/gkz454; RA Park J., Lee S.Y., Jeong H., Kang M.G., Van Haute L., Minczuk M., Seo J.K., RA Jun Y., Myung K., Rhee H.W., Lee C.; RT "The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain RT that discriminates substrates via metal coordination."; RL Nucleic Acids Res. 47:7078-7093(2019). CC -!- FUNCTION: Exonuclease that has both 3'-5' exoribonuclease and CC exodeoxyribonuclease activities, depending on the divalent metal cation CC used as cofactor (PubMed:29335528, PubMed:31127291). In presence of CC Mg(2+), only shows 3'-5' exoribonuclease activity, while it shows both CC exoribonuclease and exodeoxyribonuclease activities in presence of CC Mn(2+) (PubMed:29335528, PubMed:31127291). Acts as an exoribonuclease CC in mitochondrion, possibly by regulating ATP production and CC mitochondrial translation (PubMed:29335528). Also involved in the CC response to DNA damage (PubMed:26807646, PubMed:31255466). Acts as 3'- CC 5' exodeoxyribonuclease for double-strand breaks resection and CC efficient homologous recombination (PubMed:20603073, PubMed:26807646). CC Plays a key role in controlling the initial steps of chromosomal break CC repair, it is recruited to chromatin in a damage-dependent manner and CC functionally interacts with the MRN complex to accelerate resection CC through its 3'-5' exonuclease activity, which efficiently processes CC double-stranded DNA substrates containing nicks (PubMed:26807646). Also CC involved in response to replicative stress: recruited to stalled forks CC and is required to stabilize and restart stalled replication forks by CC restraining excessive fork regression, thereby suppressing their CC degradation (PubMed:31255466). {ECO:0000269|PubMed:20603073, CC ECO:0000269|PubMed:26807646, ECO:0000269|PubMed:29335528, CC ECO:0000269|PubMed:31127291, ECO:0000269|PubMed:31255466}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Exonucleolytic cleavage in the 3'- to 5'-direction to yield CC nucleoside 5'-phosphates.; EC=3.1.11.1; CC Evidence={ECO:0000269|PubMed:26807646, ECO:0000269|PubMed:31127291}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:29335528, ECO:0000269|PubMed:31127291}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:29335528, ECO:0000269|PubMed:31127291}; CC Note=Divalent metal cations; Mg(2+) or Mn(2+) (PubMed:31127291). Acts CC as a 3'-5' exoribonuclease in presence of Mg(2+), while it has no 3'-5' CC exodeoxyribonuclease activity (PubMed:29335528, PubMed:31127291). Has CC both as a 3'-5' exoribonuclease and exodeoxyribonuclease activities in CC presence of Mn(2+) (PubMed:31127291). {ECO:0000269|PubMed:29335528, CC ECO:0000269|PubMed:31127291}; CC -!- SUBUNIT: Homodimer (PubMed:31127291). Interacts with RBBP8, MRE11 and CC BRCA1 (PubMed:26807646). {ECO:0000269|PubMed:26807646, CC ECO:0000269|PubMed:31127291}. CC -!- INTERACTION: CC Q9NVH0; Q99708: RBBP8; NbExp=3; IntAct=EBI-11324738, EBI-745715; CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000269|PubMed:29599527, ECO:0000269|PubMed:31127291}; Single-pass CC membrane protein {ECO:0000255, ECO:0000269|PubMed:31127291}. CC Mitochondrion matrix {ECO:0000269|PubMed:29335528}. Nucleus CC {ECO:0000269|PubMed:26807646}. Chromosome {ECO:0000269|PubMed:26807646, CC ECO:0000269|PubMed:31255466}. Note=Mainly localizes to the CC mitochondrial outer membrane (PubMed:29599527, PubMed:31127291). May CC translocate to the nucleus in response to DNA damage; however mechanism CC that explain nuclear localization are unknown and require experimental CC evidences (PubMed:26807646). Recruited to replication forks following CC replication stress (PubMed:31255466). {ECO:0000269|PubMed:26807646, CC ECO:0000269|PubMed:29599527, ECO:0000269|PubMed:31127291, CC ECO:0000269|PubMed:31255466}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NVH0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NVH0-2; Sequence=VSP_044367; CC -!- SIMILARITY: Belongs to the EXD2 family. {ECO:0000305}. CC -!- CAUTION: Subcellular location is subject to discussion. Different CC publications report a mitochondrial localization (PubMed:29335528, CC PubMed:29599527, PubMed:31127291). According to some reports, CC tranlocates to the nucleus in response of DNA damage (PubMed:26807646, CC PubMed:31255466). However, according to another publication, DNA damage CC does not result in nuclear translocation (PubMed:31127291). Its precise CC localization in mitochondrion is also controversial (PubMed:29335528, CC PubMed:29599527, PubMed:31127291). Two different groups report a CC localization to the mitochondrial outer membrane, which is consistent CC with the presence of a N-terminal transmembrane region CC (PubMed:29599527, PubMed:31127291). In contrast, a publication reports CC localization to the mitochondrial matrix; protease accessibility used CC in this assay can however lead to misinterpretation if the target CC protein is unexpectedly resistant to proteases (PubMed:29335528). CC Mechanisms that explain its dual role in mitochondrion and nuclear DNA CC repair are unknown and additional evidences are needed to reconciliate CC these two apparently incompatible functions. CC {ECO:0000269|PubMed:26807646, ECO:0000269|PubMed:29335528, CC ECO:0000269|PubMed:29599527, ECO:0000269|PubMed:31127291, CC ECO:0000269|PubMed:31255466, ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAH10568.1; Type=Frameshift; 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; AK001600; BAA91781.1; -; mRNA. DR EMBL; AK295601; BAG58488.1; -; mRNA. DR EMBL; AL834434; CAD39094.2; -; mRNA. DR EMBL; BX647767; CAH10568.1; ALT_FRAME; mRNA. DR EMBL; AL359317; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471061; EAW80985.1; -; Genomic_DNA. DR EMBL; BC001962; AAH01962.1; -; mRNA. DR CCDS; CCDS53902.1; -. [Q9NVH0-1] DR CCDS; CCDS9793.1; -. [Q9NVH0-2] DR RefSeq; NP_001180289.1; NM_001193360.1. [Q9NVH0-1] DR RefSeq; NP_001180290.1; NM_001193361.1. [Q9NVH0-1] DR RefSeq; NP_001180291.1; NM_001193362.1. [Q9NVH0-1] DR RefSeq; NP_001180292.1; NM_001193363.1. [Q9NVH0-1] DR RefSeq; NP_060669.1; NM_018199.3. [Q9NVH0-2] DR RefSeq; XP_005267874.1; XM_005267817.3. [Q9NVH0-2] DR RefSeq; XP_011535210.1; XM_011536908.2. [Q9NVH0-2] DR RefSeq; XP_016876910.1; XM_017021421.1. [Q9NVH0-2] DR PDB; 6K17; X-ray; 1.60 A; A/B=76-295. DR PDB; 6K18; X-ray; 2.30 A; A/B=76-295. DR PDB; 6K19; X-ray; 2.20 A; A/B=76-295. DR PDB; 6K1A; X-ray; 2.60 A; A/B=76-295. DR PDB; 6K1B; X-ray; 2.60 A; A/B=76-295. DR PDB; 6K1C; X-ray; 2.45 A; A/B=76-295. DR PDB; 6K1D; X-ray; 3.00 A; A/B=76-295. DR PDB; 6K1E; X-ray; 2.90 A; A/B=76-295. DR PDBsum; 6K17; -. DR PDBsum; 6K18; -. DR PDBsum; 6K19; -. DR PDBsum; 6K1A; -. DR PDBsum; 6K1B; -. DR PDBsum; 6K1C; -. DR PDBsum; 6K1D; -. DR PDBsum; 6K1E; -. DR AlphaFoldDB; Q9NVH0; -. DR SMR; Q9NVH0; -. DR BioGRID; 120514; 392. DR DIP; DIP-61996N; -. DR IntAct; Q9NVH0; 25. DR MINT; Q9NVH0; -. DR STRING; 9606.ENSP00000313140; -. DR GlyGen; Q9NVH0; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9NVH0; -. DR PhosphoSitePlus; Q9NVH0; -. DR SwissPalm; Q9NVH0; -. DR BioMuta; EXD2; -. DR DMDM; 410516875; -. DR EPD; Q9NVH0; -. DR jPOST; Q9NVH0; -. DR MassIVE; Q9NVH0; -. DR MaxQB; Q9NVH0; -. DR PaxDb; 9606-ENSP00000313140; -. DR PeptideAtlas; Q9NVH0; -. DR ProteomicsDB; 33827; -. DR ProteomicsDB; 82795; -. [Q9NVH0-1] DR Pumba; Q9NVH0; -. DR TopDownProteomics; Q9NVH0-2; -. [Q9NVH0-2] DR Antibodypedia; 123; 141 antibodies from 19 providers. DR DNASU; 55218; -. DR Ensembl; ENST00000312994.9; ENSP00000313140.5; ENSG00000081177.19. [Q9NVH0-1] DR Ensembl; ENST00000409014.5; ENSP00000386915.1; ENSG00000081177.19. [Q9NVH0-2] DR Ensembl; ENST00000409018.7; ENSP00000387331.3; ENSG00000081177.19. [Q9NVH0-1] DR Ensembl; ENST00000409242.5; ENSP00000386839.1; ENSG00000081177.19. [Q9NVH0-2] DR Ensembl; ENST00000409675.5; ENSP00000386762.1; ENSG00000081177.19. [Q9NVH0-2] DR Ensembl; ENST00000409949.5; ENSP00000386632.1; ENSG00000081177.19. [Q9NVH0-2] DR Ensembl; ENST00000685843.1; ENSP00000510642.1; ENSG00000081177.19. [Q9NVH0-1] DR GeneID; 55218; -. DR KEGG; hsa:55218; -. DR MANE-Select; ENST00000685843.1; ENSP00000510642.1; NM_001193360.2; NP_001180289.1. DR UCSC; uc001xkt.4; human. [Q9NVH0-1] DR AGR; HGNC:20217; -. DR CTD; 55218; -. DR DisGeNET; 55218; -. DR GeneCards; EXD2; -. DR HGNC; HGNC:20217; EXD2. DR HPA; ENSG00000081177; Low tissue specificity. DR MIM; 616940; gene. DR neXtProt; NX_Q9NVH0; -. DR OpenTargets; ENSG00000081177; -. DR PharmGKB; PA164719421; -. DR VEuPathDB; HostDB:ENSG00000081177; -. DR eggNOG; KOG4373; Eukaryota. DR GeneTree; ENSGT00390000014318; -. DR HOGENOM; CLU_019718_0_0_1; -. DR InParanoid; Q9NVH0; -. DR OMA; TPKENQC; -. DR OrthoDB; 8362at2759; -. DR PhylomeDB; Q9NVH0; -. DR TreeFam; TF324246; -. DR PathwayCommons; Q9NVH0; -. DR SignaLink; Q9NVH0; -. DR BioGRID-ORCS; 55218; 10 hits in 1147 CRISPR screens. DR ChiTaRS; EXD2; human. DR GenomeRNAi; 55218; -. DR Pharos; Q9NVH0; Tbio. DR PRO; PR:Q9NVH0; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9NVH0; Protein. DR Bgee; ENSG00000081177; Expressed in cortical plate and 208 other cell types or tissues. DR ExpressionAtlas; Q9NVH0; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0045111; C:intermediate filament cytoskeleton; IDA:HPA. DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0090734; C:site of DNA damage; IDA:UniProtKB. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB. DR GO; GO:0008296; F:3'-5'-DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0000175; F:3'-5'-RNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB. DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0008310; F:single-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0000729; P:DNA double-strand break processing; IDA:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IDA:UniProtKB. DR GO; GO:0090304; P:nucleic acid metabolic process; IDA:UniProtKB. DR GO; GO:0031297; P:replication fork processing; IMP:UniProtKB. DR CDD; cd06141; WRN_exo; 1. DR Gene3D; 3.30.420.10; Ribonuclease H-like superfamily/Ribonuclease H; 1. DR InterPro; IPR002562; 3'-5'_exonuclease_dom. DR InterPro; IPR012337; RNaseH-like_sf. DR InterPro; IPR036397; RNaseH_sf. DR PANTHER; PTHR13620; 3-5 EXONUCLEASE; 1. DR PANTHER; PTHR13620:SF104; EXONUCLEASE 3'-5' DOMAIN-CONTAINING PROTEIN 2; 1. DR Pfam; PF01612; DNA_pol_A_exo1; 1. DR SMART; SM00474; 35EXOc; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR Genevisible; Q9NVH0; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Chromosome; DNA damage; DNA repair; KW Exonuclease; Hydrolase; Magnesium; Manganese; Membrane; Metal-binding; KW Mitochondrion; Mitochondrion outer membrane; Nuclease; Nucleus; KW Reference proteome; Transmembrane; Transmembrane helix. FT CHAIN 1..621 FT /note="Exonuclease 3'-5' domain-containing protein 2" FT /id="PRO_0000089924" FT TOPO_DOM 1..4 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305|PubMed:31127291" FT TRANSMEM 5..25 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 26..621 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:31127291" FT DOMAIN 155..247 FT /note="3'-5' exonuclease" FT /evidence="ECO:0000255" FT REGION 34..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 299..343 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 34..48 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 52..68 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 108 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31127291, FT ECO:0007744|PDB:6K18, ECO:0007744|PDB:6K1A, FT ECO:0007744|PDB:6K1B, ECO:0007744|PDB:6K1D, FT ECO:0007744|PDB:6K1E" FT BINDING 108 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31127291, FT ECO:0007744|PDB:6K19, ECO:0007744|PDB:6K1A, FT ECO:0007744|PDB:6K1B, ECO:0007744|PDB:6K1C, FT ECO:0007744|PDB:6K1D, ECO:0007744|PDB:6K1E" FT BINDING 110 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31127291, FT ECO:0007744|PDB:6K18, ECO:0007744|PDB:6K1A, FT ECO:0007744|PDB:6K1B, ECO:0007744|PDB:6K1D, FT ECO:0007744|PDB:6K1E" FT BINDING 246 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31127291, FT ECO:0007744|PDB:6K18, ECO:0007744|PDB:6K1A, FT ECO:0007744|PDB:6K1B, ECO:0007744|PDB:6K1D, FT ECO:0007744|PDB:6K1E" FT VAR_SEQ 1..125 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:17974005" FT /id="VSP_044367" FT VARIANT 231 FT /note="D -> N (in dbSNP:rs35010854)" FT /id="VAR_050980" FT VARIANT 518 FT /note="Q -> H (in dbSNP:rs8007859)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:17974005" FT /id="VAR_050981" FT MUTAGEN 108..110 FT /note="DCE->ACA: Loss of 3'-5' exonuclease activity. FT Impaired ability to stabilize and restart stalled FT replication forks in response to replication stress." FT /evidence="ECO:0000269|PubMed:26807646, FT ECO:0000269|PubMed:31255466" FT MUTAGEN 190 FT /note="R->A: Abolished exodeoxyribonuclease activity." FT /evidence="ECO:0000269|PubMed:31127291" FT MUTAGEN 195 FT /note="R->A: Impaired exonuclease activity." FT /evidence="ECO:0000269|PubMed:31127291" FT MUTAGEN 197 FT /note="R->A: Impaired exonuclease activity." FT /evidence="ECO:0000269|PubMed:31127291" FT MUTAGEN 221 FT /note="K->A: Impaired exonuclease activity." FT /evidence="ECO:0000269|PubMed:31127291" FT MUTAGEN 226 FT /note="R->A: Abolished exonuclease activity." FT /evidence="ECO:0000269|PubMed:31127291" FT CONFLICT 287 FT /note="V -> G (in Ref. 2; CAD39094)" FT /evidence="ECO:0000305" FT STRAND 79..82 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 85..98 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 100..102 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 104..110 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 123..127 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 133..136 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 138..141 FT /evidence="ECO:0007829|PDB:6K17" FT TURN 143..145 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 150..157 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 161..167 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 168..179 FT /evidence="ECO:0007829|PDB:6K17" FT STRAND 186..188 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 189..202 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 207..215 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 225..227 FT /evidence="ECO:0007829|PDB:6K18" FT STRAND 232..234 FT /evidence="ECO:0007829|PDB:6K18" FT HELIX 237..257 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 276..284 FT /evidence="ECO:0007829|PDB:6K17" FT HELIX 285..287 FT /evidence="ECO:0007829|PDB:6K19" SQ SEQUENCE 621 AA; 70353 MW; CD66A3E68A40C7FF CRC64; MSRQNLVALT VTTLLGVAVG GFVLWKGIQR RRRSKTSPVT QQPQQKVLGS RELPPPEDDQ LHSSAPRSSW KERILKAKVV TVSQEAEWDQ IEPLLRSELE DFPVLGIDCE WVNLEGKASP LSLLQMASPS GLCVLVRLPK LICGGKTLPR TLLDILADGT ILKVGVGCSE DASKLLQDYG LVVRGCLDLR YLAMRQRNNL LCNGLSLKSL AETVLNFPLD KSLLLRCSNW DAETLTEDQV IYAARDAQIS VALFLHLLGY PFSRNSPGEK NDDHSSWRKV LEKCQGVVDI PFRSKGMSRL GEEVNGEATE SQQKPRNKKS KMDGMVPGNH QGRDPRKHKR KPLGVGYSAR KSPLYDNCFL HAPDGQPLCT CDRRKAQWYL DKGIGELVSE EPFVVKLRFE PAGRPESPGD YYLMVKENLC VVCGKRDSYI RKNVIPHEYR KHFPIEMKDH NSHDVLLLCT SCHAISNYYD NHLKQQLAKE FQAPIGSEEG LRLLEDPERR QVRSGARALL NAESLPTQRK EELLQALREF YNTDVVTEEM LQEAASLETR ISNENYVPHG LKVVQCHSQG GLRSLMQLES RWRQHFLDSM QPKHLPQQWS VDHNHQKLLR KFGEDLPIQL S //