DNSL3_MOUSE
ID DNSL3_MOUSE Reviewed; 310 AA.
AC O55070; Q91X38;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Deoxyribonuclease gamma;
DE Short=DNase gamma;
DE EC=3.1.21.-;
DE AltName: Full=DNase I homolog protein DHP2;
DE AltName: Full=Deoxyribonuclease I-like 3;
DE Short=DNase I-like 3;
DE AltName: Full=Liver and spleen DNase;
DE Short=LS-DNase;
DE Short=LSD;
DE Flags: Precursor;
GN Name=Dnase1l3 {ECO:0000312|MGI:MGI:1314633};
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 [MRNA].
RX PubMed=9714828; DOI=10.1016/s0378-1119(98)00281-9;
RA Baron W.F., Pan C.Q., Spencer S.A., Ryan A.M., Lazarus R.A., Baker K.P.;
RT "Cloning and characterization of an actin-resistant DNase I-like
RT endonuclease secreted by macrophages.";
RL Gene 215:291-301(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=C57BL/6J;
RA Shiokawa D., Tanuma S.;
RT "Characterization of the murine DNase gamma gene.";
RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=10807908; DOI=10.1074/jbc.m001087200;
RA Yakovlev A.G., Wang G., Stoica B.A., Boulares H.A., Spoonde A.Y.,
RA Yoshihara K., Smulson M.E.;
RT "A role of the Ca2+/Mg2+-dependent endonuclease in apoptosis and its
RT inhibition by poly(ADP-ribose) polymerase.";
RL J. Biol. Chem. 275:21302-21308(2000).
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12050166; DOI=10.1074/jbc.m204038200;
RA Shiokawa D., Kobayashi T., Tanuma S.;
RT "Involvement of DNase gamma in apoptosis associated with myogenic
RT differentiation of C2C12 cells.";
RL J. Biol. Chem. 277:31031-31037(2002).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12095301; DOI=10.1006/mthe.2002.0625;
RA Wilber A., Lu M., Schneider M.C.;
RT "Deoxyribonuclease I-like III is an inducible macrophage barrier to
RT liposomal transfection.";
RL Mol. Ther. 6:35-42(2002).
RN [7]
RP FUNCTION.
RX PubMed=15167901; DOI=10.1038/sj.cdd.4401454;
RA Shiokawa D., Tanuma S.;
RT "Differential DNases are selectively used in neuronal apoptosis depending
RT on the differentiation state.";
RL Cell Death Differ. 11:1112-1120(2004).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, COFACTOR, AND ACTIVITY REGULATION.
RX PubMed=15796714; DOI=10.1042/bj20042124;
RA Napirei M., Wulf S., Eulitz D., Mannherz H.G., Kloeckl T.;
RT "Comparative characterization of rat deoxyribonuclease 1 (Dnase1) and
RT murine deoxyribonuclease 1-like 3 (Dnase1l3).";
RL Biochem. J. 389:355-364(2005).
RN [9]
RP FUNCTION.
RX PubMed=17218958; DOI=10.1038/sj.cdd.4402086;
RA Shiokawa D., Shika Y., Araki S., Sunaga S., Mizuta R., Kitamura D.,
RA Tanuma S.;
RT "Stage-specific expression of DNasegamma during B-cell development and its
RT role in B-cell receptor-mediated apoptosis in WEHI-231 cells.";
RL Cell Death Differ. 14:992-1000(2007).
RN [10]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=19154352; DOI=10.1111/j.1742-4658.2008.06849.x;
RA Napirei M., Ludwig S., Mezrhab J., Kloeckl T., Mannherz H.G.;
RT "Murine serum nucleases--contrasting effects of plasmin and heparin on the
RT activities of DNase1 and DNase1-like 3 (DNase1l3).";
RL FEBS J. 276:1059-1073(2009).
RN [11]
RP FUNCTION.
RX PubMed=24312463; DOI=10.1371/journal.pone.0080223;
RA Mizuta R., Araki S., Furukawa M., Furukawa Y., Ebara S., Shiokawa D.,
RA Hayashi K., Tanuma S., Kitamura D.;
RT "DNase gamma is the effector endonuclease for internucleosomal DNA
RT fragmentation in necrosis.";
RL PLoS ONE 8:E80223-E80223(2013).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND TISSUE
RP SPECIFICITY.
RX PubMed=27293190; DOI=10.1016/j.cell.2016.05.034;
RA Sisirak V., Sally B., D'Agati V., Martinez-Ortiz W., Oezcakar Z.B.,
RA David J., Rashidfarrokhi A., Yeste A., Panea C., Chida A.S., Bogunovic M.,
RA Ivanov I.I., Quintana F.J., Sanz I., Elkon K.B., Tekin M., Yalcinkaya F.,
RA Cardozo T.J., Clancy R.M., Buyon J.P., Reizis B.;
RT "Digestion of chromatin in apoptotic cell microparticles prevents
RT autoimmunity.";
RL Cell 166:88-101(2016).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29191910; DOI=10.1126/science.aam8897;
RA Jimenez-Alcazar M., Rangaswamy C., Panda R., Bitterling J., Simsek Y.J.,
RA Long A.T., Bilyy R., Krenn V., Renne C., Renne T., Kluge S., Panzer U.,
RA Mizuta R., Mannherz H.G., Kitamura D., Herrmann M., Napirei M., Fuchs T.A.;
RT "Host DNases prevent vascular occlusion by neutrophil extracellular
RT traps.";
RL Science 358:1202-1206(2017).
RN [14]
RP VARIANT ILE-89, CHARACTERIZATION OF ILE-89, AND POSSIBLE INVOLVEMENT IN
RP SLE.
RX PubMed=12974753; DOI=10.1046/j.1365-2249.2003.02267.x;
RA Wilber A., O'Connor T.P., Lu M.L., Karimi A., Schneider M.C.;
RT "Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice.";
RL Clin. Exp. Immunol. 134:46-52(2003).
CC -!- FUNCTION: Has DNA hydrolytic activity. Is capable of both single- and
CC double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends
CC (By similarity). Can cleave chromatin to nucleosomal units and cleaves
CC nucleosomal and liposome-coated DNA (PubMed:15796714, PubMed:19154352,
CC PubMed:12095301). Acts in internucleosomal DNA fragmentation (INDF)
CC during apoptosis and necrosis. The role in apoptosis includes myogenic
CC and neuronal differentiation, and BCR-mediated clonal deletion of self-
CC reactive B cells (PubMed:12050166, PubMed:15167901, PubMed:17218958,
CC PubMed:24312463). Is active on chromatin in apoptotic cell-derived
CC membrane-coated microparticles and thus suppresses anti-DNA
CC autoimmunity (PubMed:15796714, PubMed:27293190). Together with DNASE1,
CC plays a key role in degrading neutrophil extracellular traps (NETs)
CC (PubMed:29191910). NETs are mainly composed of DNA fibers and are
CC released by neutrophils to bind pathogens during inflammation
CC (PubMed:29191910). Degradation of intravascular NETs by DNASE1 and
CC DNASE1L3 is required to prevent formation of clots that obstruct blood
CC vessels and cause organ damage following inflammation
CC (PubMed:29191910). {ECO:0000250|UniProtKB:O89107,
CC ECO:0000269|PubMed:12050166, ECO:0000269|PubMed:15167901,
CC ECO:0000269|PubMed:17218958, ECO:0000269|PubMed:24312463,
CC ECO:0000269|PubMed:27293190, ECO:0000269|PubMed:29191910,
CC ECO:0000305|PubMed:15796714}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:Q13609};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q13609};
CC -!- ACTIVITY REGULATION: Inhibited by zinc. Inhibited by heparin and
CC proteolysis by plasmin. {ECO:0000250|UniProtKB:O89107,
CC ECO:0000269|PubMed:19154352}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q13609,
CC ECO:0000269|PubMed:12050166}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q13609}. Secreted {ECO:0000269|PubMed:12095301,
CC ECO:0000269|PubMed:15796714, ECO:0000269|PubMed:27293190}.
CC Note=Contradictory reports exist about the subcellular localization
CC under normal physiological conditions. Shown to translocate to rough
CC endoplasmic reticulum and to be transported through the entire
CC secretory pathway for secretion. However, under conditions of cell
CC death, may diffuse and/or be actively transported to the nucleus.
CC {ECO:0000305|PubMed:15796714, ECO:0000305|PubMed:27293190}.
CC -!- TISSUE SPECIFICITY: Expressed at high levels in liver, spleen and
CC testes. Expressed at lower levels in heart, lungs, skeletal muscle and
CC kidney. Not expressed in brain. Predominantly expressed in macrophages;
CC at protein level. Secreted by mononuclear phagocytes.
CC {ECO:0000269|PubMed:10807908, ECO:0000269|PubMed:12050166,
CC ECO:0000269|PubMed:12095301, ECO:0000269|PubMed:27293190}.
CC -!- DEVELOPMENTAL STAGE: Expression is first detected at embryonic day 11,
CC and higher amounts were detected at days 15 and 17.
CC {ECO:0000269|PubMed:10807908}.
CC -!- PTM: Poly-ADP-ribosylated by PARP1. ADP-ribosylation negatively
CC regulates enzymatic activity during apoptosis.
CC {ECO:0000250|UniProtKB:Q13609}.
CC -!- DISRUPTION PHENOTYPE: Mice develop symptoms of the autoimmune disease
CC systemic lupus erythematosus, characterized by high titers of anti-
CC nuclear autoantibodies (ANA) directed against nucleosomes and double-
CC stranded DNA, the deposition of immune complexes in glomeruli and full-
CC blown glomerulonephritis (PubMed:27293190). Mice lacking both Dnase1
CC and Dnase1l3 show vascular occlusions following bacterial infection:
CC defects are caused by the formation of intravascular neutrophil
CC extracellular traps (NETs) clots that obstruct blood vessels and cause
CC organ damage (PubMed:29191910). {ECO:0000269|PubMed:27293190,
CC ECO:0000269|PubMed:29191910}.
CC -!- SIMILARITY: Belongs to the DNase I family. {ECO:0000305}.
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DR EMBL; AF047355; AAC35753.1; -; mRNA.
DR EMBL; U76110; AAD09222.1; -; mRNA.
DR EMBL; AY024355; AAK07733.1; -; Genomic_DNA.
DR EMBL; BC012671; AAH12671.1; -; mRNA.
DR CCDS; CCDS26807.1; -.
DR RefSeq; NP_031896.3; NM_007870.3.
DR RefSeq; XP_006517984.1; XM_006517921.3.
DR AlphaFoldDB; O55070; -.
DR SMR; O55070; -.
DR STRING; 10090.ENSMUSP00000026315; -.
DR iPTMnet; O55070; -.
DR PhosphoSitePlus; O55070; -.
DR MaxQB; O55070; -.
DR PaxDb; O55070; -.
DR PRIDE; O55070; -.
DR ProteomicsDB; 279555; -.
DR Antibodypedia; 15158; 203 antibodies from 23 providers.
DR DNASU; 13421; -.
DR Ensembl; ENSMUST00000026315; ENSMUSP00000026315; ENSMUSG00000025279.
DR GeneID; 13421; -.
DR KEGG; mmu:13421; -.
DR UCSC; uc007sem.1; mouse.
DR CTD; 1776; -.
DR MGI; MGI:1314633; Dnase1l3.
DR VEuPathDB; HostDB:ENSMUSG00000025279; -.
DR eggNOG; ENOG502QPNY; Eukaryota.
DR GeneTree; ENSGT00950000182846; -.
DR HOGENOM; CLU_043335_0_1_1; -.
DR InParanoid; O55070; -.
DR OMA; SRCDIML; -.
DR OrthoDB; 1282784at2759; -.
DR PhylomeDB; O55070; -.
DR TreeFam; TF329541; -.
DR BRENDA; 3.1.21.1; 3474.
DR BioGRID-ORCS; 13421; 3 hits in 71 CRISPR screens.
DR ChiTaRS; Dnase1l3; mouse.
DR PRO; PR:O55070; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; O55070; protein.
DR Bgee; ENSMUSG00000025279; Expressed in lumbar dorsal root ganglion and 38 other tissues.
DR Genevisible; O55070; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0004530; F:deoxyribonuclease I activity; IBA:GO_Central.
DR GO; GO:0003677; F:DNA binding; ISO:MGI.
DR GO; GO:0004520; F:endodeoxyribonuclease activity; ISO:MGI.
DR GO; GO:0004519; F:endonuclease activity; IDA:MGI.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; IDA:MGI.
DR GO; GO:0006308; P:DNA catabolic process; IBA:GO_Central.
DR GO; GO:0000737; P:DNA catabolic process, endonucleolytic; IDA:UniProtKB.
DR GO; GO:0002283; P:neutrophil activation involved in immune response; IDA:UniProtKB.
DR GO; GO:0010623; P:programmed cell death involved in cell development; IDA:MGI.
DR GO; GO:0002673; P:regulation of acute inflammatory response; IDA:UniProtKB.
DR GO; GO:0070948; P:regulation of neutrophil mediated cytotoxicity; IDA:UniProtKB.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR018057; Deoxyribonuclease-1_AS.
DR InterPro; IPR016202; DNase_I.
DR InterPro; IPR033125; DNASE_I_2.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR PIRSF; PIRSF000988; DNase_I_euk; 1.
DR PRINTS; PR00130; DNASEI.
DR SMART; SM00476; DNaseIc; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
DR PROSITE; PS00919; DNASE_I_1; 1.
DR PROSITE; PS00918; DNASE_I_2; 1.
PE 1: Evidence at protein level;
KW ADP-ribosylation; Apoptosis; Calcium; Disulfide bond; Endonuclease;
KW Endoplasmic reticulum; Hydrolase; Necrosis; Nuclease; Nucleus;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..25
FT /evidence="ECO:0000250"
FT CHAIN 26..310
FT /note="Deoxyribonuclease gamma"
FT /id="PRO_0000007289"
FT REGION 289..310
FT /note="Not required for free DNA-nuclease activity but
FT required for activity towards liposome-coated DNA"
FT /evidence="ECO:0000269|PubMed:12095301"
FT MOTIF 40..56
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 301..307
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT ACT_SITE 105
FT /evidence="ECO:0000250|UniProtKB:P00639"
FT ACT_SITE 160
FT /evidence="ECO:0000250|UniProtKB:P00639"
FT DISULFID 199..236
FT /note="Essential for enzymatic activity"
FT /evidence="ECO:0000269|PubMed:15796714"
FT VARIANT 89
FT /note="T -> I (in strain: DBA/2, NZB and NZW, in vitro
FT decreases nuclease activity against free DNA by
FT approximately twofold and decreases activity to establish a
FT barrier to liposomal gene transfection by eightfold)"
FT /evidence="ECO:0000269|PubMed:12974753"
SQ SEQUENCE 310 AA; 35760 MW; BE483821E045E374 CRC64;
MSLHPASPRL ASLLLFILAL HDTLALRLCS FNVRSFGASK KENHEAMDII VKIIKRCDLI
LLMEIKDSSN NICPMLMEKL NGNSRRSTTY NYVISSRLGR NTYKEQYAFV YKEKLVSVKT
KYHYHDYQDG DTDVFSREPF VVWFHSPFTA VKDFVIVPLH TTPETSVKEI DELVDVYTDV
RSQWKTENFI FMGDFNAGCS YVPKKAWQNI RLRTDPKFVW LIGDQEDTTV KKSTSCAYDR
IVLCGQEIVN SVVPRSSGVF DFQKAYDLSE EEALDVSDHF PVEFKLQSSR AFTNNRKSVS
LKKRKKGNRS
