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NUCG_HUMAN
ID   NUCG_HUMAN              Reviewed;         297 AA.
AC   Q14249; Q5T281; Q9BSP2;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   11-JAN-2011, sequence version 4.
DT   03-AUG-2022, entry version 173.
DE   RecName: Full=Endonuclease G, mitochondrial;
DE            Short=Endo G;
DE            EC=3.1.30.-;
DE   Flags: Precursor;
GN   Name=ENDOG;
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 [MRNA].
RC   TISSUE=Brain;
RA   Zeviani M.;
RL   Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164053; DOI=10.1038/nature02465;
RA   Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA   Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA   Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA   Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA   Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA   Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA   Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA   Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA   Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA   Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA   Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA   Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA   Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA   Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA   Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA   McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA   Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA   Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA   Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA   Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA   West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA   Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA   Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA   Dunham I.;
RT   "DNA sequence and analysis of human chromosome 9.";
RL   Nature 429:369-374(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-12.
RC   TISSUE=Brain, and Uterus;
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   NUCLEOTIDE SEQUENCE [MRNA] OF 75-297.
RC   TISSUE=Brain;
RX   PubMed=7789991; DOI=10.1016/0888-7543(95)80058-t;
RA   Tiranti V., Rossi E., Ruiz-Carrillo A., Rossi G., Rocchi M., Didonato S.,
RA   Zuffardi O., Zeviani M.;
RT   "Chromosomal localization of mitochondrial transcription factor A (TCF6),
RT   single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG),
RT   three human housekeeping genes involved in mitochondrial biogenesis.";
RL   Genomics 25:559-564(1995).
RN   [5]
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   [6]
RP   FUNCTION.
RX   PubMed=25355512; DOI=10.1093/nar/gku1032;
RA   Robertson A.B., Robertson J., Fusser M., Klungland A.;
RT   "Endonuclease G preferentially cleaves 5-hydroxymethylcytosine-modified DNA
RT   creating a substrate for recombination.";
RL   Nucleic Acids Res. 42:13280-13293(2014).
RN   [7]
RP   FUNCTION.
RX   PubMed=29719607; DOI=10.18632/oncotarget.24822;
RA   Wiehe R.S., Gole B., Chatre L., Walther P., Calzia E., Ricchetti M.,
RA   Wiesmueller L.;
RT   "Endonuclease G promotes mitochondrial genome cleavage and replication.";
RL   Oncotarget 9:18309-18326(2018).
RN   [8]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH YWHAG, PHOSPHORYLATION AT
RP   THR-128 AND SER-288, AND MUTAGENESIS OF THR-128 AND SER-288.
RX   PubMed=33473107; DOI=10.1038/s41467-020-20780-2;
RA   Wang W., Li J., Tan J., Wang M., Yang J., Zhang Z.M., Li C.,
RA   Basnakian A.G., Tang H.W., Perrimon N., Zhou Q.;
RT   "Endonuclease G promotes autophagy by suppressing mTOR signaling and
RT   activating the DNA damage response.";
RL   Nat. Commun. 12:476-476(2021).
CC   -!- FUNCTION: Endonuclease that preferentially catalyzes the cleavage of
CC       double-stranded 5-hydroxymethylcytosine (5hmC)-modified DNA
CC       (PubMed:25355512). The 5hmC-modified nucleotide does not increase the
CC       binding affinity, but instead increases the efficiency of cutting and
CC       specifies the site of cleavage for the modified DNAs (By similarity).
CC       Shows significantly higher affinity for four-stranded Holliday junction
CC       over duplex and single-stranded DNAs (By similarity). Promotes
CC       conservative recombination when the DNA is 5hmC-modified
CC       (PubMed:25355512). Promotes autophagy through the suppression of mTOR
CC       by its phosphorylation-mediated interaction with YWHAG and its
CC       endonuclease activity-mediated DNA damage response (PubMed:33473107).
CC       GSK3-beta mediated phosphorylation of ENDOG enhances its interaction
CC       with YWHAG, leading to the release of TSC2 and PIK3C3 from YWHAG
CC       resulting in mTOR pathway suppression and autophagy initiation
CC       (PubMed:33473107). Promotes cleavage of mtDNA in response to oxidative
CC       and nitrosative stress, in turn inducing compensatory mtDNA replication
CC       (PubMed:29719607). {ECO:0000250|UniProtKB:O08600,
CC       ECO:0000269|PubMed:25355512, ECO:0000269|PubMed:29719607,
CC       ECO:0000269|PubMed:33473107}.
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:O08600};
CC   -!- SUBUNIT: Homodimer; disulfide-linked (By similarity). Homodimerization
CC       is essential for enzyme activity (By similarity). Interacts with YWHAG
CC       (PubMed:33473107). {ECO:0000250|UniProtKB:O08600,
CC       ECO:0000269|PubMed:33473107}.
CC   -!- INTERACTION:
CC       Q14249; Q8WW22: DNAJA4; NbExp=2; IntAct=EBI-9369928, EBI-2555157;
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:33473107}.
CC   -!- PTM: GSK3-beta-mediated dual phosphorylations at Thr-128 and Ser-288 is
CC       necessary for its interaction with YWHAG and the induction of
CC       autophagy. {ECO:0000269|PubMed:33473107}.
CC   -!- SIMILARITY: Belongs to the DNA/RNA non-specific endonuclease family.
CC       {ECO:0000305}.
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DR   EMBL; X79444; CAA55963.1; -; mRNA.
DR   EMBL; AL441992; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC004922; AAH04922.1; -; mRNA.
DR   EMBL; BC016351; AAH16351.1; -; mRNA.
DR   CCDS; CCDS6912.1; -.
DR   PIR; T09542; T09542.
DR   RefSeq; NP_004426.2; NM_004435.2.
DR   AlphaFoldDB; Q14249; -.
DR   SMR; Q14249; -.
DR   BioGRID; 108336; 77.
DR   IntAct; Q14249; 28.
DR   MINT; Q14249; -.
DR   STRING; 9606.ENSP00000361725; -.
DR   ChEMBL; CHEMBL3804749; -.
DR   iPTMnet; Q14249; -.
DR   PhosphoSitePlus; Q14249; -.
DR   BioMuta; ENDOG; -.
DR   DMDM; 317373579; -.
DR   EPD; Q14249; -.
DR   jPOST; Q14249; -.
DR   MassIVE; Q14249; -.
DR   MaxQB; Q14249; -.
DR   PaxDb; Q14249; -.
DR   PeptideAtlas; Q14249; -.
DR   PRIDE; Q14249; -.
DR   ProteomicsDB; 59950; -.
DR   Antibodypedia; 17709; 489 antibodies from 40 providers.
DR   DNASU; 2021; -.
DR   Ensembl; ENST00000372642.5; ENSP00000361725.4; ENSG00000167136.7.
DR   GeneID; 2021; -.
DR   KEGG; hsa:2021; -.
DR   MANE-Select; ENST00000372642.5; ENSP00000361725.4; NM_004435.2; NP_004426.2.
DR   UCSC; uc004bwc.4; human.
DR   CTD; 2021; -.
DR   DisGeNET; 2021; -.
DR   GeneCards; ENDOG; -.
DR   HGNC; HGNC:3346; ENDOG.
DR   HPA; ENSG00000167136; Tissue enhanced (skeletal).
DR   MIM; 600440; gene.
DR   neXtProt; NX_Q14249; -.
DR   OpenTargets; ENSG00000167136; -.
DR   PharmGKB; PA27783; -.
DR   VEuPathDB; HostDB:ENSG00000167136; -.
DR   eggNOG; KOG3721; Eukaryota.
DR   GeneTree; ENSGT00940000160987; -.
DR   HOGENOM; CLU_055174_0_1_1; -.
DR   InParanoid; Q14249; -.
DR   OMA; YVMPNQV; -.
DR   OrthoDB; 933605at2759; -.
DR   PhylomeDB; Q14249; -.
DR   TreeFam; TF105386; -.
DR   PathwayCommons; Q14249; -.
DR   SignaLink; Q14249; -.
DR   SIGNOR; Q14249; -.
DR   BioGRID-ORCS; 2021; 38 hits in 1078 CRISPR screens.
DR   GeneWiki; ENDOG; -.
DR   GenomeRNAi; 2021; -.
DR   Pharos; Q14249; Tbio.
DR   PRO; PR:Q14249; -.
DR   Proteomes; UP000005640; Chromosome 9.
DR   RNAct; Q14249; protein.
DR   Bgee; ENSG00000167136; Expressed in hindlimb stylopod muscle and 177 other tissues.
DR   ExpressionAtlas; Q14249; baseline and differential.
DR   Genevisible; Q14249; HS.
DR   GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR   GO; GO:0004520; F:endodeoxyribonuclease activity; IMP:UniProtKB.
DR   GO; GO:0004519; F:endonuclease activity; IBA:GO_Central.
DR   GO; GO:0004521; F:endoribonuclease activity; IBA:GO_Central.
DR   GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR   GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR   GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR   GO; GO:0000014; F:single-stranded DNA endodeoxyribonuclease activity; IBA:GO_Central.
DR   GO; GO:0007568; P:aging; IEA:Ensembl.
DR   GO; GO:0006309; P:apoptotic DNA fragmentation; IBA:GO_Central.
DR   GO; GO:0071277; P:cellular response to calcium ion; IEA:Ensembl.
DR   GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR   GO; GO:0006310; P:DNA recombination; TAS:UniProtKB.
DR   GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR   GO; GO:0032043; P:mitochondrial DNA catabolic process; IMP:UniProtKB.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB.
DR   GO; GO:0036475; P:neuron death in response to oxidative stress; IEA:Ensembl.
DR   GO; GO:1902512; P:positive regulation of apoptotic DNA fragmentation; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR   GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; IEA:Ensembl.
DR   GO; GO:0090297; P:positive regulation of mitochondrial DNA replication; IMP:UniProtKB.
DR   GO; GO:2001022; P:positive regulation of response to DNA damage stimulus; IMP:UniProtKB.
DR   GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR   GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR   GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR   GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR   Gene3D; 3.40.570.10; -; 1.
DR   InterPro; IPR018524; DNA/RNA_endonuclease_AS.
DR   InterPro; IPR001604; DNA/RNA_non-sp_Endonuclease.
DR   InterPro; IPR044929; DNA/RNA_non-sp_Endonuclease_sf.
DR   InterPro; IPR020821; Extracellular_endonuc_su_A.
DR   InterPro; IPR044925; His-Me_finger_sf.
DR   InterPro; IPR040255; Non-specific_endonuclease.
DR   PANTHER; PTHR13966; PTHR13966; 1.
DR   Pfam; PF01223; Endonuclease_NS; 1.
DR   SMART; SM00892; Endonuclease_NS; 1.
DR   SMART; SM00477; NUC; 1.
DR   SUPFAM; SSF54060; SSF54060; 1.
DR   PROSITE; PS01070; NUCLEASE_NON_SPEC; 1.
PE   1: Evidence at protein level;
KW   Disulfide bond; Endonuclease; Hydrolase; Magnesium; Manganese;
KW   Metal-binding; Mitochondrion; Nuclease; Phosphoprotein; Reference proteome;
KW   Transit peptide.
FT   TRANSIT         1..48
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000250"
FT   CHAIN           49..297
FT                   /note="Endonuclease G, mitochondrial"
FT                   /id="PRO_0000019918"
FT   REGION          286..296
FT                   /note="Essential for deoxyribonuclease activity"
FT                   /evidence="ECO:0000250|UniProtKB:O08600"
FT   ACT_SITE        141
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10047"
FT   BINDING         172
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:O08600"
FT   SITE            110
FT                   /note="Essential for catalytic activity"
FT                   /evidence="ECO:0000250|UniProtKB:O08600"
FT   MOD_RES         128
FT                   /note="Phosphothreonine; by GSK3-beta"
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   MOD_RES         288
FT                   /note="Phosphoserine; by GSK3-beta"
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   DISULFID        113
FT                   /note="Interchain"
FT                   /evidence="ECO:0000250|UniProtKB:O08600"
FT   VARIANT         12
FT                   /note="S -> L (in dbSNP:rs2293969)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_031691"
FT   MUTAGEN         128
FT                   /note="T->A: Loss of phosphorylation. Suppresses
FT                   interaction with YWHAG and induction of autophagy; when
FT                   associated with A-288."
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   MUTAGEN         128
FT                   /note="T->D: Phosphomimetic mutant. No effect on its
FT                   interaction with YWHAG. Enhances interaction with YWHAG;
FT                   when associated with T-288."
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   MUTAGEN         288
FT                   /note="S->A: Loss of phosphorylation. Suppresses
FT                   interaction with YWHAG and induction of autophagy; when
FT                   associated with A-128."
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   MUTAGEN         288
FT                   /note="S->D: Phosphomimetic mutant. No effect on its
FT                   interaction with YWHAG. Enhances interaction with YWHAG;
FT                   when associated with T-128."
FT                   /evidence="ECO:0000269|PubMed:33473107"
FT   CONFLICT        34
FT                   /note="P -> L (in Ref. 1; CAA55963)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        163
FT                   /note="N -> K (in Ref. 1; CAA55963)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   297 AA;  32620 MW;  33015E8A619781B7 CRC64;
     MRALRAGLTL ASGAGLGAVV EGWRRRREDA RAAPGLLGRL PVLPVAAAAE LPPVPGGPRG
     PGELAKYGLP GLAQLKSRES YVLCYDPRTR GALWVVEQLR PERLRGDGDR RECDFREDDS
     VHAYHRATNA DYRGSGFDRG HLAAAANHRW SQKAMDDTFY LSNVAPQVPH LNQNAWNNLE
     KYSRSLTRSY QNVYVCTGPL FLPRTEADGK SYVKYQVIGK NHVAVPTHFF KVLILEAAGG
     QIELRTYVMP NAPVDEAIPL ERFLVPIESI ERASGLLFVP NILARAGSLK AITAGSK
 
 
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