RN168_BOVIN
ID RN168_BOVIN Reviewed; 573 AA.
AC Q0IIM1;
DT 24-MAR-2009, integrated into UniProtKB/Swiss-Prot.
DT 24-MAR-2009, sequence version 2.
DT 03-AUG-2022, entry version 99.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford;
RX PubMed=19390049; DOI=10.1126/science.1169588;
RG The bovine genome sequencing and analysis consortium;
RT "The genome sequence of taurine cattle: a window to ruminant biology and
RT evolution.";
RL Science 324:522-528(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=Hereford; TISSUE=Thalamus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
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 -!- 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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q0IIM1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q0IIM1-2; Sequence=VSP_036673, VSP_036674;
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}.
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DR EMBL; AAFC03087522; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAFC03087524; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC122577; AAI22578.1; -; mRNA.
DR RefSeq; NP_001069757.2; NM_001076289.2.
DR AlphaFoldDB; Q0IIM1; -.
DR SMR; Q0IIM1; -.
DR STRING; 9913.ENSBTAP00000017712; -.
DR PaxDb; Q0IIM1; -.
DR PRIDE; Q0IIM1; -.
DR Ensembl; ENSBTAT00000074288; ENSBTAP00000067959; ENSBTAG00000013317. [Q0IIM1-2]
DR GeneID; 613812; -.
DR KEGG; bta:613812; -.
DR CTD; 165918; -.
DR VEuPathDB; HostDB:ENSBTAG00000013317; -.
DR eggNOG; KOG4159; Eukaryota.
DR GeneTree; ENSGT00940000153680; -.
DR InParanoid; Q0IIM1; -.
DR OrthoDB; 458276at2759; -.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000009136; Chromosome 1.
DR Bgee; ENSBTAG00000013317; Expressed in semen and 107 other tissues.
DR ExpressionAtlas; Q0IIM1; baseline and differential.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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; IBA:GO_Central.
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: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; ISS: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: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; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF00097; zf-C3HC4; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Chromatin regulator; DNA damage; DNA repair;
KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Transferase; Ubl conjugation; Ubl conjugation pathway;
KW Zinc; Zinc-finger.
FT CHAIN 1..573
FT /note="E3 ubiquitin-protein ligase RNF168"
FT /id="PRO_0000367281"
FT ZN_FING 16..55
FT /note="RING-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT REGION 153..174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 196..277
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 456..528
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 540..573
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 440..463
FT /note="MIU motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 467..478
FT /note="LR motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT COMPBIAS 213..246
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 247..270
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 474..489
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 490..519
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80XJ2"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:B2RYR0"
FT MOD_RES 363
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:B2RYR0"
FT MOD_RES 416
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT MOD_RES 471
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 530
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT VAR_SEQ 187..190
FT /note="NNFC -> VFVT (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_036673"
FT VAR_SEQ 191..573
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_036674"
SQ SEQUENCE 573 AA; 65894 MW; 28931B25A25E687A CRC64;
MAVPKESIPS LLECQCQICV EILFEPVTLP CNHTLCKPCF ESTVEKASLC CPFCRRRVSS
WARYRSRTNS LVNMELWEII QKHYPKECKL RASGQESKEI VDDYQPVRLL SKPGELRREY
EEEISKVEAE RRACEEEENK ASEEYIQKLL AEEEEEEKRQ AEKRHREMEE QLKSDEELAR
RLSLDINNFC EGSVLASPLN SRKSDPVTTK SQKKSKNKQT NTGDIQKYLS PKSQLGSASQ
SEVVQEDRKS SMSKKIDDNS DVKSPTWQDT EVEEDMPTLS PQIYLEVQEQ GAKSSVESPM
PQLYTSDGEW YLEGKVETGP SNHEKGLCVI NLEEPKARVP YSGDAATEPC GETESECTVS
YMTQFLRNNT VGTENEESHL QISKGTSKRR NLEPLSEAIR EPCFSAKRRK MFPKASSDQE
ETEISLTQKL IDLEHLLFER HKQEKQDRLL ALQLQEEVDQ EQMRPDRQKG SPDGYQLRTV
SSPPDKVLNG QRKNSRDRNS KRQTELEQPK PRTDSKNENH QQPSFKIQLK CSVNRRKIAN
STNDNCNVSK TAHSLQPSKS QKSIFQMFQR VTK
