RN168_RAT
ID RN168_RAT Reviewed; 564 AA.
AC B2RYR0;
DT 24-MAR-2009, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-2008, sequence version 1.
DT 25-MAY-2022, entry version 94.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-348 AND THR-361, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT regulation of aquaporin-2 phosphorylation at two sites.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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 -!- 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; BC166869; AAI66869.1; -; mRNA.
DR RefSeq; NP_001121069.2; NM_001127597.2.
DR AlphaFoldDB; B2RYR0; -.
DR SMR; B2RYR0; -.
DR STRING; 10116.ENSRNOP00000002395; -.
DR iPTMnet; B2RYR0; -.
DR PaxDb; B2RYR0; -.
DR GeneID; 690043; -.
DR KEGG; rno:690043; -.
DR UCSC; RGD:1585168; rat.
DR CTD; 165918; -.
DR RGD; 1585168; Rnf168.
DR eggNOG; KOG4159; Eukaryota.
DR HOGENOM; CLU_030653_1_0_1; -.
DR InParanoid; B2RYR0; -.
DR OrthoDB; 458276at2759; -.
DR PhylomeDB; B2RYR0; -.
DR Reactome; R-RNO-3108214; SUMOylation of DNA damage response and repair proteins.
DR Reactome; R-RNO-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR Reactome; R-RNO-5693571; Nonhomologous End-Joining (NHEJ).
DR Reactome; R-RNO-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-RNO-69473; G2/M DNA damage checkpoint.
DR UniPathway; UPA00143; -.
DR PRO; PR:B2RYR0; -.
DR Proteomes; UP000002494; Unplaced.
DR Genevisible; B2RYR0; RN.
DR GO; GO:1990391; C:DNA repair complex; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
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:RGD.
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; ISO:RGD.
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:0032880; P:regulation of protein localization; ISO:RGD.
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 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..564
FT /note="E3 ubiquitin-protein ligase RNF168"
FT /id="PRO_0000367282"
FT ZN_FING 16..55
FT /note="RING-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT REGION 149..179
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 193..291
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 455..564
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 193..226
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 244..260
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 261..288
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 467..485
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 488..518
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 521..537
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 546..564
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80XJ2"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 348
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:16641100"
FT MOD_RES 361
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:16641100"
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 524
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8IYW5"
SQ SEQUENCE 564 AA; 64404 MW; 4975BF9E08445E71 CRC64;
MAAPKNSIPS LAECQCGICM EILVEPVTLP CNHTLCNPCF QSTVEKANLC CPFCRRRVSS
WTRYHTRRNS LVNTDLWEII QKHYAKECKL RISGQESKEI VDEYQPVRLL SKPGELRREY
EEEISKVEAE RQASKEEENK ASEEYIQRLL AEEEEEEKRR TERRRSEMEE QLRGDEELAR
RLSTSINSNY ERNILASPLS SRKSDPVTNK SQKKNTNKQK NFGDIQRYLS PKSKPGTAWA
CKTEHGEDMC KSKETDSSDT KSPVLQDTDV EESMPTHSPQ TCPETQGQGP EPLTEMPVPW
LCARNAEQCL EGKAEAVSTN PDDSCIVNDG GPRAIVSNSK EAAVKPPTKI ENEEYSVSGV
TQLTGGNGVP TESRVYDLLV GKEISERENQ ESVFEEVMDP CFSAKRRKIF ITSSLDQEET
EVNFTQKLID LEHMLFERHK QEEQDRLLAL QLQKEADKEK MVPNRQKGSP DQYQLRTSSP
PDGLLNGQRK NVKDRNSPKQ TADRSKSQRS RKGEYWETFE STWKGSVNGT KMPTPRKDSC
NVSKRACPLQ HRSAQKSILQ MFQR
