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Protein

E3 ubiquitin-protein ligase RNF168

Gene

RNF168

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 annotation8 Publications

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 binding Source: UniProtKB
  • ligase activity Source: UniProtKB-KW
  • nucleosome binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: UniProtKB
  • zinc ion binding Source: InterPro

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 sumoylation Source: Reactome
  • protein ubiquitination Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Ligase

Keywords - Biological processi

DNA damage, DNA repair, Ubl conjugation pathway

Keywords - Ligandi

Metal-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:6.3.2.-UniRule annotation)
Short name:
hRNF168
Alternative name(s):
RING finger protein 168UniRule annotation
Gene namesi
Name:RNF168UniRule annotation
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:26661. RNF168.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: HPA
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • protein complex Source: MGI
  • site of double-strand break Source: UniProtKB
  • ubiquitin ligase complex Source: UniProtKB
Complete GO annotation...

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
Modified residuei362PhosphothreonineBy similarity1
Modified residuei411PhosphoserineCombined sources1
Modified residuei414PhosphoserineCombined sources1
Modified residuei415PhosphoserineCombined sources1
Modified residuei470PhosphoserineCombined sources1

Post-translational modificationi

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

Keywords - PTMi

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

WithEntry#Exp.IntActNotes
UBE2NP610882EBI-914207,EBI-1052908

GO - Molecular functioni

  • histone binding Source: UniProtKB
  • K63-linked polyubiquitin binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi127922. 42 interactors.
DIPiDIP-37451N.
IntActiQ8IYW5. 20 interactors.
MINTiMINT-1180501.
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

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[»]
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
Contains 1 RING-type zinc finger.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.
InterProiIPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS50089. ZF_RING_2. 1 hit.
[Graphical view]

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 rs35774921dbSNPEnsembl.1
Natural variantiVAR_026997401P → Q.1 PublicationCorresponds to variant rs3796129dbSNPEnsembl.1
Natural variantiVAR_052110413E → K.Corresponds to variant rs6790173dbSNPEnsembl.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

Cross-referencesi

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.

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[»]
ProteinModelPortaliQ8IYW5.
SMRiQ8IYW5.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi127922. 42 interactors.
DIPiDIP-37451N.
IntActiQ8IYW5. 20 interactors.
MINTiMINT-1180501.
STRINGi9606.ENSP00000320898.

PTM databases

iPTMnetiQ8IYW5.
PhosphoSitePlusiQ8IYW5.

Polymorphism and mutation databases

BioMutaiRNF168.
DMDMi74762499.

Proteomic databases

EPDiQ8IYW5.
MaxQBiQ8IYW5.
PaxDbiQ8IYW5.
PeptideAtlasiQ8IYW5.
PRIDEiQ8IYW5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi165918.
DisGeNETi165918.
GeneCardsiRNF168.
HGNCiHGNC:26661. RNF168.
HPAiHPA046109.
MalaCardsiRNF168.
MIMi611943. phenotype.
612688. gene.
neXtProtiNX_Q8IYW5.
OpenTargetsiENSG00000163961.
PharmGKBiPA134945219.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

UniPathwayiUPA00143.
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.

Miscellaneous databases

ChiTaRSiRNF168. human.
EvolutionaryTraceiQ8IYW5.
GenomeRNAii165918.
PROiQ8IYW5.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000163961.
CleanExiHS_RNF168.
ExpressionAtlasiQ8IYW5. baseline and differential.
GenevisibleiQ8IYW5. HS.

Family and domain databases

Gene3Di3.30.40.10. 1 hit.
HAMAPiMF_03066. RNF168. 1 hit.
InterProiIPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRN168_HUMAN
AccessioniPrimary (citable) accession number: Q8IYW5
Secondary accession number(s): Q8NA67, Q96NS4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 11, 2006
Last sequence update: March 1, 2003
Last modified: November 30, 2016
This is version 133 of the entry and version 1 of the sequence. [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

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

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.