SPRTN_MOUSE
ID SPRTN_MOUSE Reviewed; 497 AA.
AC G3X912; B2RY42;
DT 03-OCT-2012, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 1.
DT 03-AUG-2022, entry version 65.
DE RecName: Full=DNA-dependent metalloprotease SPRTN {ECO:0000305};
DE EC=3.4.24.- {ECO:0000250|UniProtKB:Q9H040};
DE AltName: Full=Protein with SprT-like domain at the N terminus {ECO:0000250|UniProtKB:Q9H040};
DE Short=Spartan {ECO:0000250|UniProtKB:Q9H040};
GN Name=Sprtn {ECO:0000312|MGI:MGI:2685351};
GN Synonyms=Gm505 {ECO:0000312|MGI:MGI:2685351};
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 DISRUPTION PHENOTYPE.
RX PubMed=25501849; DOI=10.1038/ncomms6744;
RA Maskey R.S., Kim M.S., Baker D.J., Childs B., Malureanu L.A.,
RA Jeganathan K.B., Machida Y., van Deursen J.M., Machida Y.J.;
RT "Spartan deficiency causes genomic instability and progeroid phenotypes.";
RL Nat. Commun. 5:5744-5744(2014).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28199696; DOI=10.1093/nar/gkx107;
RA Maskey R.S., Flatten K.S., Sieben C.J., Peterson K.L., Baker D.J.,
RA Nam H.J., Kim M.S., Smyrk T.C., Kojima Y., Machida Y., Santiago A.,
RA van Deursen J.M., Kaufmann S.H., Machida Y.J.;
RT "Spartan deficiency causes accumulation of Topoisomerase 1 cleavage
RT complexes and tumorigenesis.";
RL Nucleic Acids Res. 45:4564-4576(2017).
RN [6]
RP FUNCTION.
RX PubMed=27871365; DOI=10.1016/j.molcel.2016.09.031;
RA Stingele J., Bellelli R., Alte F., Hewitt G., Sarek G., Maslen S.L.,
RA Tsutakawa S.E., Borg A., Kjaer S., Tainer J.A., Skehel J.M., Groll M.,
RA Boulton S.J.;
RT "Mechanism and regulation of DNA-protein crosslink repair by the DNA-
RT dependent metalloprotease SPRTN.";
RL Mol. Cell 64:688-703(2016).
CC -!- FUNCTION: DNA-dependent metalloendopeptidase that mediates the
CC proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during
CC DNA synthesis, thereby playing a key role in maintaining genomic
CC integrity (PubMed:28199696, PubMed:27871365). DPCs are highly toxic DNA
CC lesions that interfere with essential chromatin transactions, such as
CC replication and transcription, and which are induced by reactive
CC agents, such as UV light or formaldehyde (PubMed:28199696,
CC PubMed:27871365). Associates with the DNA replication machinery and
CC specifically removes DPCs during DNA synthesis. Acts as a pleiotropic
CC protease for DNA-binding proteins cross-linked with DNA, such as TOP1,
CC TOP2A, histones H3 and H4 (By similarity). Mediates degradation of DPCs
CC that are not ubiquitinated, while it is not able to degrade
CC ubiquitinated DPCs. SPRTN activation requires polymerase collision with
CC DPCs followed by helicase bypass of DPCs (By similarity). Involved in
CC recruitment of VCP/p97 to sites of DNA damage. Also acts as an
CC activator of CHEK1 during normal DNA replication by mediating
CC proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from
CC chromatin and subsequent activation. Does not activate CHEK1 in
CC response to DNA damage. May also act as a 'reader' of ubiquitinated
CC PCNA: recruited to sites of UV damage and interacts with ubiquitinated
CC PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA.
CC Facilitates chromatin association of RAD18 and is required for
CC efficient PCNA monoubiquitination, promoting a feed-forward loop to
CC enhance PCNA ubiquitination and translesion DNA synthesis (By
CC similarity). {ECO:0000250|UniProtKB:A0A1L8G2K9,
CC ECO:0000250|UniProtKB:Q9H040, ECO:0000269|PubMed:27871365,
CC ECO:0000269|PubMed:28199696}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q9H040};
CC -!- ACTIVITY REGULATION: DNA-binding activates the protease activity:
CC single-stranded DNA-binding specifically activates ability to cleave
CC covalent DNA-protein cross-links (DPCs). In contrast, double-stranded
CC DNA-binding specifically activates autocatalytic cleavage, and
CC subsequent inactivation. {ECO:0000250|UniProtKB:Q9H040}.
CC -!- SUBUNIT: Homodimer. Interacts (VIA PIP-box) with PCNA (when
CC ubiquitinated). Interacts (via its SHP-box) with VCP/p97. Interacts
CC with RAD18. Interacts with KCTD13 and POLD3.
CC {ECO:0000250|UniProtKB:Q9H040}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9H040}.
CC Chromosome {ECO:0000250|UniProtKB:Q9H040}. Note=Localizes to sites of
CC UV damage via the PIP-box. Recruited to stalled replication forks at
CC sites of replication stress following deubiquitination. CHEK1
CC stimulates recruitment to chromatin. {ECO:0000250|UniProtKB:Q9H040}.
CC -!- DOMAIN: The PIP-box mediates the interaction with PCNA, while the UBZ4-
CC type zinc finger mediates binding to 'Lys-48'- and 'Lys-63'-linked
CC polyubiquitin. {ECO:0000250|UniProtKB:Q9H040}.
CC -!- PTM: Autocatalytically cleaved in response to double-stranded DNA-
CC binding: autocatalytic cleavage takes place in trans and leads to
CC inactivation. {ECO:0000250|UniProtKB:Q9H040}.
CC -!- PTM: Monoubiquitinated; monoubiquitination promotes exclusion from
CC chromatin. Deubiquitinated by VCPIP1: deubiquitination is required for
CC subsequent acetylation and recruitment to chromatin and DNA damage
CC sites. {ECO:0000250|UniProtKB:Q9H040}.
CC -!- PTM: Acetylated following deubiquitination by VCPIP1, leading to
CC recruitment to chromatin and DNA damage sites.
CC {ECO:0000250|UniProtKB:Q9H040}.
CC -!- PTM: Phosphorylation by CHEK1 promotes recruitment to chromatin.
CC {ECO:0000250|UniProtKB:Q9H040}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality caused by genomic instability
CC (PubMed:25501849). Cells display impaired lesion bypass, incomplete DNA
CC replication, formation of micronuclei and chromatin bridges and
CC eventually cell death (PubMed:25501849). Cells show an accumulation of
CC DNA-protein cross-links (DPCs) (PubMed:28199696). Sprtn-
CC haploinsufficient mice are viable but show accelerated aging,
CC characterized by cataracts, lordokyphosis and cachexia at a young age
CC (PubMed:25501849). {ECO:0000269|PubMed:25501849,
CC ECO:0000269|PubMed:28199696}.
CC -!- SIMILARITY: Belongs to the Spartan family. {ECO:0000305}.
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DR EMBL; AC139158; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466525; EDL11789.1; -; Genomic_DNA.
DR EMBL; BC158088; AAI58089.1; -; mRNA.
DR CCDS; CCDS52705.1; -.
DR RefSeq; NP_001104611.1; NM_001111141.1.
DR AlphaFoldDB; G3X912; -.
DR SMR; G3X912; -.
DR BioGRID; 232674; 1.
DR STRING; 10090.ENSMUSP00000034467; -.
DR iPTMnet; G3X912; -.
DR PhosphoSitePlus; G3X912; -.
DR EPD; G3X912; -.
DR MaxQB; G3X912; -.
DR PaxDb; G3X912; -.
DR PRIDE; G3X912; -.
DR ProteomicsDB; 257328; -.
DR Antibodypedia; 20798; 135 antibodies from 19 providers.
DR Ensembl; ENSMUST00000034467; ENSMUSP00000034467; ENSMUSG00000031986.
DR GeneID; 244666; -.
DR KEGG; mmu:244666; -.
DR UCSC; uc009nxx.2; mouse.
DR CTD; 83932; -.
DR MGI; MGI:2685351; Sprtn.
DR VEuPathDB; HostDB:ENSMUSG00000031986; -.
DR eggNOG; KOG3931; Eukaryota.
DR GeneTree; ENSGT00390000003585; -.
DR HOGENOM; CLU_019426_2_0_1; -.
DR InParanoid; G3X912; -.
DR OMA; AYLFITN; -.
DR OrthoDB; 1171375at2759; -.
DR PhylomeDB; G3X912; -.
DR TreeFam; TF314762; -.
DR Reactome; R-MMU-110320; Translesion Synthesis by POLH.
DR BioGRID-ORCS; 244666; 22 hits in 107 CRISPR screens.
DR PRO; PR:G3X912; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; G3X912; protein.
DR Bgee; ENSMUSG00000031986; Expressed in spermatocyte and 210 other tissues.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB.
DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; IBA:GO_Central.
DR GO; GO:0003697; F:single-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR GO; GO:0106300; P:protein-DNA covalent cross-linking repair; IMP:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR GO; GO:0009411; P:response to UV; ISS:UniProtKB.
DR GO; GO:0019985; P:translesion synthesis; ISS:UniProtKB.
DR InterPro; IPR006642; Rad18_UBZ4.
DR InterPro; IPR044245; Spartan.
DR InterPro; IPR006640; SprT-like_domain.
DR PANTHER; PTHR21220; PTHR21220; 1.
DR Pfam; PF10263; SprT-like; 1.
DR SMART; SM00731; SprT; 1.
DR SMART; SM00734; ZnF_Rad18; 1.
DR PROSITE; PS51908; ZF_UBZ4; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Autocatalytic cleavage; Chromosome; DNA damage; DNA repair;
KW Hydrolase; Isopeptide bond; Metal-binding; Metalloprotease; Nucleus;
KW Phosphoprotein; Protease; Reference proteome; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..497
FT /note="DNA-dependent metalloprotease SPRTN"
FT /id="PRO_0000419484"
FT DOMAIN 46..213
FT /note="SprT-like"
FT /evidence="ECO:0000255"
FT ZN_FING 462..489
FT /note="UBZ4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01256"
FT REGION 344..459
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 254..262
FT /note="SHP-box"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOTIF 326..333
FT /note="PIP-box"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOTIF 413..424
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT COMPBIAS 344..364
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 372..410
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 411..430
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 431..459
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 113
FT /evidence="ECO:0000250|UniProtKB:Q9H040,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 112
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9H040,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 116
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9H040,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 131
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT BINDING 465
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01256"
FT BINDING 468
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01256"
FT BINDING 480
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01256"
FT BINDING 484
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01256"
FT SITE 228..229
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOD_RES 231
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOD_RES 269
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT MOD_RES 384
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CROSSLNK 304
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CROSSLNK 342
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CROSSLNK 342
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CROSSLNK 362
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CROSSLNK 432
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H040"
FT CONFLICT 413
FT /note="D -> N (in Ref. 3; AAI58089)"
FT /evidence="ECO:0000305"
FT CONFLICT 442
FT /note="R -> Q (in Ref. 3; AAI58089)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 497 AA; 55317 MW; 92B47BFBFD4616C6 CRC64;
MDEDLVVALR LQEEWDVQMA RRAAAAREPV SLVDASWELV DPTPDLQALF LQFNDRFFWG
QLEAVEVKWS VRMTLCAGIC TYEGRGGMCS IRLSEPLLKL RPRKDLVETL LHEMIHAYLF
VTNNDKDREG HGPEFCKHMH RINQLTGANI TVYHTFHDEV DEYRRHWWRC NGPCQHRQPY
YGYVKRATNR APSVHDYWWA DHQKTCGGTY IKIKEPENYS KKGRGKTKAD KQPASAVENK
DKLCRGEAQL LIPFSGKGYV LGDASTCPSA GKLNTSYMVN EAKGLSSQDH SVSGLRLNSN
AEVKCEQNCL PKKPHLVSPL PTASHQSVLS SYFPRVSVAN QKAFRNVNGS PVKNGTTGDG
TKRPASGGSQ RKVPPSRASL RNTSKVTAPA SATVTSAAGT SATISREESG SEDQFLNKRP
RLEDRTALDT IKEQTQSGGD LRSSSQPTAA SAPQSLSSQR RLVNCPVCQG VVVESQINEH
LDRCLEGNKT NLRPRRV
