EXD2_HUMAN
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 03-AUG-2022, entry version 164.
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},
GN EXDL2 {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};
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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; 381.
DR DIP; DIP-61996N; -.
DR IntAct; Q9NVH0; 22.
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 BioMuta; EXD2; -.
DR DMDM; 410516875; -.
DR EPD; Q9NVH0; -.
DR jPOST; Q9NVH0; -.
DR MassIVE; Q9NVH0; -.
DR MaxQB; Q9NVH0; -.
DR PaxDb; Q9NVH0; -.
DR PeptideAtlas; Q9NVH0; -.
DR PRIDE; Q9NVH0; -.
DR ProteomicsDB; 33827; -.
DR ProteomicsDB; 82795; -. [Q9NVH0-1]
DR TopDownProteomics; Q9NVH0-2; -. [Q9NVH0-2]
DR Antibodypedia; 123; 121 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 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 OMA; RYYQTPK; -.
DR OrthoDB; 692844at2759; -.
DR PhylomeDB; Q9NVH0; -.
DR TreeFam; TF324246; -.
DR PathwayCommons; Q9NVH0; -.
DR SignaLink; Q9NVH0; -.
DR BioGRID-ORCS; 55218; 10 hits in 1071 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 207 other tissues.
DR ExpressionAtlas; Q9NVH0; baseline and differential.
DR Genevisible; Q9NVH0; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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'-exodeoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0000175; F:3'-5'-exoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0008852; F:exodeoxyribonuclease I activity; IEA:UniProtKB-EC.
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' exodeoxyribonuclease 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:0090305; P:nucleic acid phosphodiester bond hydrolysis; IDA:UniProtKB.
DR GO; GO:0031297; P:replication fork processing; IMP:UniProtKB.
DR Gene3D; 3.30.420.10; -; 1.
DR InterPro; IPR002562; 3'-5'_exonuclease_dom.
DR InterPro; IPR012337; RNaseH-like_sf.
DR InterPro; IPR036397; RNaseH_sf.
DR Pfam; PF01612; DNA_pol_A_exo1; 1.
DR SMART; SM00474; 35EXOc; 1.
DR SUPFAM; SSF53098; SSF53098; 1.
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
