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Protein

E3 ubiquitin-protein ligase RNF168

Gene

RNF168

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).UniRule annotation9 Publications

Caution

According to a well-established model, RNF168 cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19500350, PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidences are however required to confirm these data.UniRule annotation1 Publication

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.UniRule annotation

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.UniRule annotation
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri16 – 55RING-typeUniRule annotationAdd BLAST40

GO - Molecular functioni

  • chromatin binding Source: UniProtKB
  • histone binding Source: UniProtKB
  • K63-linked polyubiquitin modification-dependent protein binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • nucleosome binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • double-strand break repair Source: UniProtKB
  • double-strand break repair via nonhomologous end joining Source: Reactome
  • histone H2A-K13 ubiquitination Source: UniProtKB
  • histone H2A-K15 ubiquitination Source: UniProtKB
  • histone H2A K63-linked ubiquitination Source: UniProtKB
  • histone H2A monoubiquitination Source: UniProtKB
  • interstrand cross-link repair Source: UniProtKB
  • isotype switching Source: UniProtKB
  • negative regulation of transcription elongation from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of DNA repair Source: UniProtKB
  • protein K63-linked ubiquitination Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB

Keywordsi

Molecular functionChromatin regulator, Transferase
Biological processDNA damage, DNA repair, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-3108214 SUMOylation of DNA damage response and repair proteins
R-HSA-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571 Nonhomologous End-Joining (NHEJ)
R-HSA-5693607 Processing of DNA double-strand break ends
R-HSA-69473 G2/M DNA damage checkpoint
SIGNORiQ8IYW5
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase RNF168UniRule annotation (EC:2.3.2.27UniRule annotation)
Short name:
hRNF168
Alternative name(s):
RING finger protein 168UniRule annotation
RING-type E3 ubiquitin transferase RNF168
Gene namesi
Name:RNF168UniRule annotation
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000163961.4
HGNCiHGNC:26661 RNF168
MIMi612688 gene
neXtProtiNX_Q8IYW5

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Riddle syndrome (RIDDLES)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionCharacterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Defects are probably due to impaired localization of TP53BP1 and BRCA1 at DNA lesions.
See also OMIM:611943

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi16C → S: Does not affect ability to bind ubiquitin and localization to DSBs sites, while it abolishes E3 ligase activity; when associated with S-19. 1 Publication1
Mutagenesisi18I → A: Abolishes ability to ubiquitinate KDM4A. 1 Publication1
Mutagenesisi19C → S: Does not affect ability to bind ubiquitin and localization to DSBs sites, while it abolishes E3 ligase activity; when associated with S-16. 1 Publication1
Mutagenesisi57R → D: Does not affect the monomeric structure but abolishes ability to monoubiquitinate H2A in nucleosomes. 1 Publication1
Mutagenesisi149 – 150LL → AA: Impaired ability to bind ubiquitin. 1 Publication2
Mutagenesisi179A → G: Impairs ability to form foci following ionizing radiation and impaired binding to 'Lys-63'-linked ubiquitin. 3 Publications1
Mutagenesisi450A → G: Still able to bind 'Lys-63'-linked ubiquitin. 3 Publications1
Mutagenesisi476 – 477LR → AA: Does not affect ubiquitin-binding but impairs recruitment to DSBs. 1 Publication2

Organism-specific databases

DisGeNETi165918
MalaCardsiRNF168
MIMi611943 phenotype
OpenTargetsiENSG00000163961
PharmGKBiPA134945219

Polymorphism and mutation databases

BioMutaiRNF168
DMDMi74762499

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002455961 – 571E3 ubiquitin-protein ligase RNF168Add BLAST571

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei70PhosphoserineBy similarity1
Modified residuei134PhosphoserineCombined sources1
Modified residuei197PhosphoserineBy similarity1
Cross-linki210Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei362PhosphothreonineBy similarity1
Modified residuei411PhosphoserineCombined sources1
Modified residuei414PhosphoserineCombined sources1
Modified residuei415PhosphoserineCombined sources1
Modified residuei470PhosphoserineCombined sources1
Cross-linki528Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs).UniRule annotation1 Publication
Ubiquitinated.UniRule annotation2 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8IYW5
MaxQBiQ8IYW5
PaxDbiQ8IYW5
PeptideAtlasiQ8IYW5
PRIDEiQ8IYW5

PTM databases

iPTMnetiQ8IYW5
PhosphoSitePlusiQ8IYW5

Expressioni

Gene expression databases

BgeeiENSG00000163961
CleanExiHS_RNF168
ExpressionAtlasiQ8IYW5 baseline and differential
GenevisibleiQ8IYW5 HS

Organism-specific databases

HPAiHPA046109

Interactioni

Subunit structurei

Monomer. Interacts with UBE2N/UBC13.UniRule annotation2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • histone binding Source: UniProtKB
  • K63-linked polyubiquitin modification-dependent protein binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi127922, 64 interactors
DIPiDIP-37451N
IntActiQ8IYW5, 25 interactors
MINTiQ8IYW5
STRINGi9606.ENSP00000320898

Structurei

Secondary structure

1571
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi11 – 14Combined sources4
Turni17 – 19Combined sources3
Beta strandi24 – 28Combined sources5
Beta strandi34 – 36Combined sources3
Helixi37 – 43Combined sources7
Turni44 – 48Combined sources5
Turni52 – 54Combined sources3
Helixi59 – 67Combined sources9
Helixi74 – 83Combined sources10
Helixi85 – 93Combined sources9
Helixi115 – 187Combined sources73
Helixi419 – 455Combined sources37

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3L11X-ray2.12A1-113[»]
4GB0X-ray2.60A1-111[»]
5XISX-ray1.78A/D110-188[»]
5XITX-ray2.25A/E113-188[»]
5XIUX-ray1.80A419-462[»]
5YDKX-ray2.50A/F/G/L113-194[»]
ProteinModelPortaliQ8IYW5
SMRiQ8IYW5
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8IYW5

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi110 – 128LR motif 1UniRule annotationAdd BLAST19
Motifi143 – 151UMI motifUniRule annotation9
Motifi168 – 191MIU motif 1UniRule annotationAdd BLAST24
Motifi439 – 462MIU motif 2UniRule annotationAdd BLAST24
Motifi466 – 477LR motif 2UniRule annotationAdd BLAST12

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi115 – 177Glu-richUniRule annotationAdd BLAST63

Domaini

The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).UniRule annotation3 Publications

Sequence similaritiesi

Belongs to the RNF168 family.UniRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri16 – 55RING-typeUniRule annotationAdd BLAST40

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4159 Eukaryota
COG2802 LUCA
GeneTreeiENSGT00730000111120
HOGENOMiHOG000154156
HOVERGENiHBG067220
InParanoidiQ8IYW5
KOiK20779
OMAiHKQEEQD
OrthoDBiEOG091G0FWX
PhylomeDBiQ8IYW5
TreeFamiTF332796

Family and domain databases

Gene3Di3.30.40.10, 1 hit
HAMAPiMF_03066 RNF168, 1 hit
InterProiView protein in InterPro
IPR034725 RNF168
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
SMARTiView protein in SMART
SM00184 RING, 1 hit
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit

Sequencei

Sequence statusi: Complete.

Q8IYW5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MALPKDAIPS LSECQCGICM EILVEPVTLP CNHTLCKPCF QSTVEKASLC
60 70 80 90 100
CPFCRRRVSS WTRYHTRRNS LVNVELWTII QKHYPRECKL RASGQESEEV
110 120 130 140 150
ADDYQPVRLL SKPGELRREY EEEISKVAAE RRASEEEENK ASEEYIQRLL
160 170 180 190 200
AEEEEEEKRQ AEKRRRAMEE QLKSDEELAR KLSIDINNFC EGSISASPLN
210 220 230 240 250
SRKSDPVTPK SEKKSKNKQR NTGDIQKYLT PKSQFGSASH SEAVQEVRKD
260 270 280 290 300
SVSKDIDSSD RKSPTGQDTE IEDMPTLSPQ ISLGVGEQGA DSSIESPMPW
310 320 330 340 350
LCACGAEWYH EGNVKTRPSN HGKELCVLSH ERPKTRVPYS KETAVMPCGR
360 370 380 390 400
TESGCAPTSG VTQTNGNNTG ETENEESCLL ISKEISKRKN QESSFEAVKD
410 420 430 440 450
PCFSAKRRKV SPESSPDQEE TEINFTQKLI DLEHLLFERH KQEEQDRLLA
460 470 480 490 500
LQLQKEVDKE QMVPNRQKGS PDEYHLRATS SPPDKVLNGQ RKNPKDGNFK
510 520 530 540 550
RQTHTKHPTP ERGSRDKNRQ VSLKMQLKQS VNRRKMPNST RDHCKVSKSA
560 570
HSLQPSISQK SVFQMFQRCT K
Length:571
Mass (Da):65,020
Last modified:March 1, 2003 - v1
Checksum:i51E16DA92BA654C1
GO

Sequence cautioni

The sequence BAC04060 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti9P → L in BAB70801 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_034466387K → R. Corresponds to variant dbSNP:rs35774921Ensembl.1
Natural variantiVAR_026997401P → Q1 PublicationCorresponds to variant dbSNP:rs3796129EnsemblClinVar.1
Natural variantiVAR_052110413E → K. Corresponds to variant dbSNP:rs6790173EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK054732 mRNA Translation: BAB70801.1
AK093113 mRNA Translation: BAC04060.1 Different initiation.
AC092933 Genomic DNA No translation available.
AC117490 Genomic DNA No translation available.
BC033791 mRNA Translation: AAH33791.1
CCDSiCCDS3317.1
RefSeqiNP_689830.2, NM_152617.3
UniGeneiHs.250648

Genome annotation databases

EnsembliENST00000318037; ENSP00000320898; ENSG00000163961
GeneIDi165918
KEGGihsa:165918
UCSCiuc003fwq.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiRN168_HUMAN
AccessioniPrimary (citable) accession number: Q8IYW5
Secondary accession number(s): Q8NA67, Q96NS4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 11, 2006
Last sequence update: March 1, 2003
Last modified: May 23, 2018
This is version 146 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

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