NUCG_MOUSE
ID NUCG_MOUSE Reviewed; 294 AA.
AC O08600;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=Endonuclease G, mitochondrial;
DE Short=Endo G;
DE EC=3.1.30.-;
DE Flags: Precursor;
GN Name=Endog;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC STRAIN=129/Sv, and BALB/cJ; TISSUE=Brain;
RX PubMed=9324313; DOI=10.1089/dna.1997.16.1111;
RA Prats E., Noel M., Letourneau J., Tiranti V., Vaque J., Debon R.,
RA Zeviani M., Cornudella L., Ruiz-Carrillo A.;
RT "Characterization and expression of the mouse endonuclease G gene.";
RL DNA Cell Biol. 16:1111-1122(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=C57BL/6J; TISSUE=Heart;
RA Matsuda T.;
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
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 [6]
RP FUNCTION.
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).
RN [7] {ECO:0007744|PDB:6LYF, ECO:0007744|PDB:6M3F, ECO:0007744|PDB:6M3T}
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 45-293 OF MUTANTS ALA-110 AND
RP ALA-138, FUNCTION, SUBUNIT, COFACTOR, ACTIVE SITE, METAL-BINDING SITES,
RP DISULFIDE BOND, AND MUTAGENESIS OF ARG-107; CYS-110 AND HIS-138.
RX PubMed=32192768; DOI=10.1016/j.bbrc.2020.03.060;
RA Park K.H., Yoon S.M., Song H.N., Yang J.H., Ryu S.E., Woo E.J.;
RT "Crystal structure of the mouse endonuclease G.";
RL Biochem. Biophys. Res. Commun. 526:35-40(2020).
RN [8] {ECO:0007744|PDB:6NJT, ECO:0007744|PDB:6NJU}
RP X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) OF 43-294 OF MUTANT ALA-138 IN
RP COMPLEX WITH DNA, FUNCTION, SUBUNIT, COFACTOR, ACTIVE SITE, METAL-BINDING
RP SITES, DISULFIDE BOND, AND MUTAGENESIS OF CYS-110.
RX PubMed=32095813; DOI=10.1093/nar/gkaa117;
RA Vander Zanden C.M., Czarny R.S., Ho E.N., Robertson A.B., Ho P.S.;
RT "Structural adaptation of vertebrate endonuclease G for 5-
RT hydroxymethylcytosine recognition and function.";
RL Nucleic Acids Res. 48:3962-3974(2020).
CC -!- FUNCTION: Endonuclease that preferentially catalyzes the cleavage of
CC double-stranded 5-hydroxymethylcytosine (5hmC)-modified DNA
CC (PubMed:25355512, PubMed:32095813). The 5hmC-modified nucleotide does
CC not increase the binding affinity, but instead increases the efficiency
CC of cutting and specifies the site of cleavage for the modified DNAs
CC (PubMed:32095813). Shows significantly higher affinity for four-
CC stranded Holliday junction over duplex and single-stranded DNAs
CC (PubMed:32095813). Promotes conservative recombination when the DNA is
CC 5hmC-modified (PubMed:25355512). Promotes autophagy through the
CC suppression of mTOR by its phosphorylation-mediated interaction with
CC YWHAG and its endonuclease activity-mediated DNA damage response
CC (PubMed:33473107). GSK3-beta mediated phosphorylation of ENDOG enhances
CC its interaction with YWHAG, leading to the release of TSC2 and PIK3C3
CC from YWHAG resulting in mTOR pathway suppression and autophagy
CC initiation (By similarity). Promotes cleavage of mtDNA in response to
CC oxidative and nitrosative stress, in turn inducing compensatory mtDNA
CC replication (By similarity). {ECO:0000250|UniProtKB:Q14249,
CC ECO:0000269|PubMed:25355512, ECO:0000269|PubMed:32095813,
CC ECO:0000269|PubMed:33473107}.
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:32095813, ECO:0000269|PubMed:32192768};
CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:32192768,
CC PubMed:32095813). Homodimerization is essential for its activity
CC (PubMed:32192768). Interacts with YWHAG (By similarity).
CC {ECO:0000250|UniProtKB:Q14249, ECO:0000269|PubMed:32095813,
CC ECO:0000269|PubMed:32192768}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:Q14249}.
CC -!- PTM: GSK3-beta-mediated phosphorylation at Thr-125 is necessary for its
CC interaction with YWHAG and the induction of autophagy.
CC {ECO:0000250|UniProtKB:Q14249}.
CC -!- SIMILARITY: Belongs to the DNA/RNA non-specific endonuclease family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA67768.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; X99395; CAA67769.1; -; Genomic_DNA.
DR EMBL; X99394; CAA67768.1; ALT_INIT; mRNA.
DR EMBL; AB012108; BAA28168.1; -; mRNA.
DR EMBL; BC030177; AAH30177.1; -; mRNA.
DR CCDS; CCDS15872.1; -.
DR RefSeq; NP_031957.1; NM_007931.1.
DR PDB; 6LYF; X-ray; 2.80 A; A/B/C/D=45-293.
DR PDB; 6M3F; X-ray; 1.96 A; B/C=45-293.
DR PDB; 6M3T; X-ray; 2.38 A; A/B=45-293.
DR PDB; 6M3U; X-ray; 2.32 A; A/B/C/D=45-293.
DR PDB; 6NJT; X-ray; 2.07 A; A/B=43-294.
DR PDB; 6NJU; X-ray; 2.35 A; A/B/C/D=43-294.
DR PDBsum; 6LYF; -.
DR PDBsum; 6M3F; -.
DR PDBsum; 6M3T; -.
DR PDBsum; 6M3U; -.
DR PDBsum; 6NJT; -.
DR PDBsum; 6NJU; -.
DR AlphaFoldDB; O08600; -.
DR SMR; O08600; -.
DR BioGRID; 199449; 14.
DR STRING; 10090.ENSMUSP00000015481; -.
DR iPTMnet; O08600; -.
DR PhosphoSitePlus; O08600; -.
DR EPD; O08600; -.
DR jPOST; O08600; -.
DR PaxDb; O08600; -.
DR PeptideAtlas; O08600; -.
DR PRIDE; O08600; -.
DR ProteomicsDB; 293777; -.
DR Antibodypedia; 17709; 489 antibodies from 40 providers.
DR DNASU; 13804; -.
DR Ensembl; ENSMUST00000015481; ENSMUSP00000015481; ENSMUSG00000015337.
DR GeneID; 13804; -.
DR KEGG; mmu:13804; -.
DR UCSC; uc008jbk.1; mouse.
DR CTD; 2021; -.
DR MGI; MGI:1261433; Endog.
DR VEuPathDB; HostDB:ENSMUSG00000015337; -.
DR eggNOG; KOG3721; Eukaryota.
DR GeneTree; ENSGT00940000160987; -.
DR HOGENOM; CLU_055174_0_1_1; -.
DR InParanoid; O08600; -.
DR OMA; YVMPNQV; -.
DR OrthoDB; 933605at2759; -.
DR PhylomeDB; O08600; -.
DR TreeFam; TF105386; -.
DR BioGRID-ORCS; 13804; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Endog; mouse.
DR PRO; PR:O08600; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; O08600; protein.
DR Bgee; ENSMUSG00000015337; Expressed in heart right ventricle and 227 other tissues.
DR ExpressionAtlas; O08600; baseline and differential.
DR Genevisible; O08600; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0043204; C:perikaryon; ISO:MGI.
DR GO; GO:0004536; F:deoxyribonuclease activity; ISO:MGI.
DR GO; GO:0004520; F:endodeoxyribonuclease activity; IDA: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; IDA:UniProtKB.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0042803; F:protein homodimerization activity; IMP: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; IMP:MGI.
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:0006308; P:DNA catabolic process; TAS:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0032043; P:mitochondrial DNA catabolic process; ISS: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; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:MGI.
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; ISO:MGI.
DR GO; GO:0090297; P:positive regulation of mitochondrial DNA replication; ISS:UniProtKB.
DR GO; GO:2001022; P:positive regulation of response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0046677; P:response to antibiotic; IMP:MGI.
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; IMP:MGI.
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 3D-structure; Disulfide bond; Endonuclease; Hydrolase; Magnesium;
KW Metal-binding; Mitochondrion; Nuclease; Phosphoprotein; Reference proteome;
KW Transit peptide.
FT TRANSIT 1..44
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 45..294
FT /note="Endonuclease G, mitochondrial"
FT /id="PRO_0000019919"
FT REGION 283..293
FT /note="Essential for deoxyribonuclease activity"
FT /evidence="ECO:0000269|PubMed:32192768"
FT ACT_SITE 138
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10047,
FT ECO:0000269|PubMed:32095813, ECO:0000269|PubMed:32192768"
FT BINDING 169
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:32095813,
FT ECO:0000269|PubMed:32192768, ECO:0007744|PDB:6LYF,
FT ECO:0007744|PDB:6NJT"
FT SITE 107
FT /note="Essential for catalytic activity"
FT /evidence="ECO:0000269|PubMed:32192768"
FT MOD_RES 125
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14249"
FT DISULFID 110
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:32095813,
FT ECO:0000269|PubMed:32192768"
FT MUTAGEN 107
FT /note="R->Q: Loss of deoxyribonuclease activity."
FT /evidence="ECO:0000269|PubMed:32192768"
FT MUTAGEN 110
FT /note="C->A: Loss of homodimerization and deoxyribonuclease
FT activity. Shows a 1.3-fold higher rate for the cleavage of
FT the 5hmC-modified DNA junction over unmodified junction, as
FT compared to the 1.8-fold difference seen in the wild type
FT enzyme."
FT /evidence="ECO:0000269|PubMed:32095813,
FT ECO:0000269|PubMed:32192768"
FT MUTAGEN 110
FT /note="C->S: Shows a 2.1-fold higher rate for the cleavage
FT of the 5hmC-modified DNA junction over unmodified junction,
FT as compared to the 1.8-fold difference seen in the wild
FT type enzyme."
FT /evidence="ECO:0000269|PubMed:32095813"
FT MUTAGEN 138
FT /note="H->A: Catalytically inactive."
FT /evidence="ECO:0000269|PubMed:32095813,
FT ECO:0000269|PubMed:32192768"
FT HELIX 61..64
FT /evidence="ECO:0007829|PDB:6NJT"
FT STRAND 71..74
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 79..83
FT /evidence="ECO:0007829|PDB:6M3F"
FT TURN 84..87
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 88..96
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 98..101
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 102..105
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 116..118
FT /evidence="ECO:0007829|PDB:6LYF"
FT HELIX 120..122
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 126..129
FT /evidence="ECO:0007829|PDB:6M3F"
FT TURN 130..133
FT /evidence="ECO:0007829|PDB:6M3U"
FT STRAND 135..140
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 142..145
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 149..154
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 158..160
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 161..164
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 166..170
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 172..182
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 183..185
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 187..197
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 208..215
FT /evidence="ECO:0007829|PDB:6M3F"
FT TURN 216..219
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 224..233
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 235..237
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 239..249
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 257..260
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 264..271
FT /evidence="ECO:0007829|PDB:6M3F"
FT HELIX 276..280
FT /evidence="ECO:0007829|PDB:6M3F"
FT STRAND 282..285
FT /evidence="ECO:0007829|PDB:6M3U"
SQ SEQUENCE 294 AA; 32191 MW; 9F01FB1BC28B95D3 CRC64;
MRALRAGLTL ALGAGLGAAA EHWRRREGKA PGLLGRVPLL PVVAADLPAL PGGPAGGTGE
LAKYGLPGVA QLRSRESYVL SYDPRTRGAL WVLEQLRPER LRGDGDRSAC DFREDDSVHA
YHRATNADYR GSGFDRGHLA AAANHRWSQR AMDDTFYLSN VAPQVPHLNQ NAWNNLERYS
RSLTRTYQNV YVCTGPLFLP RTEADGKSYV KYQVIGKNHV AVPTHFFKVL ILEAAGGQIE
LRSYVMPNAP VDETIPLERF LVPIESIERA SGLLFVPNIL ARAGNLKAIT AGSK
