RN168_MOUSE
ID RN168_MOUSE Reviewed; 565 AA.
AC Q80XJ2;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 24-MAR-2009, sequence version 3.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=E3 ubiquitin-protein ligase RNF168 {ECO:0000255|HAMAP-Rule:MF_03066};
DE EC=2.3.2.27 {ECO:0000255|HAMAP-Rule:MF_03066};
DE AltName: Full=RING finger protein 168 {ECO:0000255|HAMAP-Rule:MF_03066};
DE AltName: Full=RING-type E3 ubiquitin transferase RNF168;
GN Name=Rnf168 {ECO:0000255|HAMAP-Rule:MF_03066};
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 MRNA].
RC STRAIN=C57BL/6J; 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 [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, 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 [4]
RP FUNCTION.
RX PubMed=20080757; DOI=10.1073/pnas.0913790107;
RA Ramachandran S., Chahwan R., Nepal R.M., Frieder D., Panier S., Roa S.,
RA Zaheen A., Durocher D., Scharff M.D., Martin A.;
RT "The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch
RT recombination.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:809-814(2010).
CC -!- FUNCTION: E3 ubiquitin-protein ligase required for accumulation of
CC repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to
CC amplify the RNF8-dependent histone ubiquitination. Recruited to sites
CC of DNA damage at double-strand breaks (DSBs) by binding to
CC ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A
CC ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin
CC conjugates. This leads to concentrate ubiquitinated histones H2A and
CC H2AX at DNA lesions to the threshold required for recruitment of
CC TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs)
CC sites and promotes accumulation of 'Lys-63'-linked ubiquitination of
CC histones H2A and H2AX, leading to recruitment of FAAP20 and Fanconi
CC anemia (FA) complex, followed by interstrand cross-link repair. H2A
CC ubiquitination also mediates the ATM-dependent transcriptional
CC silencing at regions flanking DSBs in cis, a mechanism to avoid
CC collision between transcription and repair intermediates. Also involved
CC in class switch recombination in immune system, via its role in
CC regulation of DSBs repair. Following DNA damage, promotes the
CC ubiquitination and degradation of JMJD2A/KDM4A in collaboration with
CC RNF8, leading to unmask H4K20me2 mark and promote the recruitment of
CC TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked
CC ubiquitination in vitro; possibly due to partial occlusion of the
CC UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13'
CC and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub,
CC respectively). {ECO:0000255|HAMAP-Rule:MF_03066,
CC ECO:0000269|PubMed:20080757}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000255|HAMAP-Rule:MF_03066};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- SUBUNIT: Monomer. Interacts with UBE2N/UBC13. {ECO:0000255|HAMAP-
CC Rule:MF_03066}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03066}.
CC Note=Localizes to double-strand breaks (DSBs) sites of DNA damage.
CC {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- DOMAIN: The MIU motif (motif interacting with ubiquitin) mediates the
CC interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains.
CC The UMI motif mediates interaction with ubiquitin with a preference for
CC 'Lys-63'-linked ubiquitin. The specificity for different types of
CC ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU
CC and UMI motifs) with LR motifs (LRMs). {ECO:0000255|HAMAP-
CC Rule:MF_03066}.
CC -!- PTM: Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks
CC (DSBs). {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- PTM: Ubiquitinated. {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- SIMILARITY: Belongs to the RNF168 family. {ECO:0000255|HAMAP-
CC Rule:MF_03066}.
CC -!- CAUTION: According to a well-established model, RNF168 cannot initiate
CC H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-
CC dependent histone ubiquitination to amplify H2A 'Lys-63'-linked
CC ubiquitination. However, other data suggest that RNF168 is the priming
CC ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-
CC 15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively).
CC These data suggest that RNF168 might be recruited to DSBs sites in a
CC RNF8-dependent manner by binding to non-histone proteins ubiquitinated
CC via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is
CC then amplified by RNF8. Additional evidence is however required to
CC confirm these data. {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH46815.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH46815.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC126265; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC046815; AAH46815.1; ALT_SEQ; mRNA.
DR RefSeq; NP_081631.2; NM_027355.2.
DR AlphaFoldDB; Q80XJ2; -.
DR SMR; Q80XJ2; -.
DR BioGRID; 213933; 3.
DR STRING; 10090.ENSMUSP00000126484; -.
DR iPTMnet; Q80XJ2; -.
DR PhosphoSitePlus; Q80XJ2; -.
DR EPD; Q80XJ2; -.
DR jPOST; Q80XJ2; -.
DR MaxQB; Q80XJ2; -.
DR PaxDb; Q80XJ2; -.
DR PRIDE; Q80XJ2; -.
DR ProteomicsDB; 299840; -.
DR Antibodypedia; 33941; 235 antibodies from 30 providers.
DR DNASU; 70238; -.
DR Ensembl; ENSMUST00000014218; ENSMUSP00000014218; ENSMUSG00000014074.
DR GeneID; 70238; -.
DR KEGG; mmu:70238; -.
DR CTD; 165918; -.
DR MGI; MGI:1917488; Rnf168.
DR VEuPathDB; HostDB:ENSMUSG00000014074; -.
DR eggNOG; KOG4159; Eukaryota.
DR GeneTree; ENSGT00940000153680; -.
DR InParanoid; Q80XJ2; -.
DR OrthoDB; 458276at2759; -.
DR Reactome; R-MMU-3108214; SUMOylation of DNA damage response and repair proteins.
DR Reactome; R-MMU-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR Reactome; R-MMU-5693571; Nonhomologous End-Joining (NHEJ).
DR Reactome; R-MMU-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-MMU-69473; G2/M DNA damage checkpoint.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 70238; 20 hits in 108 CRISPR screens.
DR ChiTaRS; Rnf168; mouse.
DR PRO; PR:Q80XJ2; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; Q80XJ2; protein.
DR Bgee; ENSMUSG00000014074; Expressed in animal zygote and 227 other tissues.
DR ExpressionAtlas; Q80XJ2; baseline and differential.
DR Genevisible; Q80XJ2; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:1990391; C:DNA repair complex; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0042393; F:histone 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:0031491; F:nucleosome binding; ISO:MGI.
DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; IDA:MGI.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR GO; GO:0070535; P:histone H2A K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0035518; P:histone H2A monoubiquitination; ISS:UniProtKB.
DR GO; GO:0036351; P:histone H2A-K13 ubiquitination; ISS:UniProtKB.
DR GO; GO:0036352; P:histone H2A-K15 ubiquitination; ISS:UniProtKB.
DR GO; GO:0045190; P:isotype switching; IMP:UniProtKB.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0045739; P:positive regulation of DNA repair; ISS:UniProtKB.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0032880; P:regulation of protein localization; IMP:MGI.
DR GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR HAMAP; MF_03066; RNF168; 1.
DR InterPro; IPR034725; RNF168.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Chromatin regulator; DNA damage; DNA repair; Isopeptide bond;
KW Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..565
FT /note="E3 ubiquitin-protein ligase RNF168"
FT /id="PRO_0000245597"
FT ZN_FING 16..55
FT /note="RING-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT REGION 150..223
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 252..302
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 458..521
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 110..128
FT /note="LR motif 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 143..151
FT /note="UMI motif"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 168..191
FT /note="MIU motif 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 438..461
FT /note="MIU motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 465..476
FT /note="LR motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT COMPBIAS 150..177
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 178..223
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 252..266
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 267..295
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 465..485
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:B2RYR0"
FT MOD_RES 413
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT MOD_RES 414
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT MOD_RES 469
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT CROSSLNK 210
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT CROSSLNK 525
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
SQ SEQUENCE 565 AA; 64779 MW; F862617604CB1229 CRC64;
MAAPKTSIPS LAECQCGICM EILLEPVTLP CNHTLCNPCF QSTVEKANLC CPFCRRRVSS
WTRYHTRRNS LVNTDLWEII QKHYAKECKL RISGQESKEI IDECQPVRRL SEPGELRREY
EEEISRVEAE RQASKEEENK ASEEYIQRLL AEEEEEEKRQ REKRRSEMEE QLRGDEELAR
SLSTSINSNY ERNTLASPLS SRKSDPVTNK SQKKNTSKQK TFGDIQKYLS PKLKPGTALA
CKAELEEDIC KSKETDRSDT KSPVLQDTEI EKNIPTLSPQ TCLETQEQGS ESSAGIPGPQ
LCVGDTKESL EGKVETVSTS PDDLCIVNDD GPRATVFYSN EAAVNSSSKI ENEEYSVTGV
PQLTGGNRVP TESRVYHLLV EEEISDRENQ ESVFEEVMDP CFSAKRRKIF IESSSDQEET
EVNFTQKLID LEHMLFERHK QEEQDRLLAL QLQKEVDKEQ MVPNRQKGSP DQYQLRTPSP
PDRLLNRQRK NSKDRNSLQQ TNADHSKSPR NTKGDYWEPF KNTWKDSVNG TKMPTSTQDN
CNVSKSAYTV QHRKSQRSIV QMFQR
