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Protein

E3 ubiquitin-protein ligase RNF8

Gene

Rnf8

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20 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. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites (By similarity). Following DNA damage, mediates the ubiquitination and degradation of POLD4/p12, a subunit of DNA polymerase delta. In the absence of POLD4, DNA polymerase delta complex exhibits higher proofreading activity (By similarity). In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggravating telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2 (By similarity).UniRule annotationBy similarity

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 fingeri405 – 443RING-typeUniRule annotationAdd BLAST39

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Ligase

Keywords - Biological processi

Cell cycle, Cell division, DNA damage, DNA repair, Mitosis, Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-RNO-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-RNO-5693571. Nonhomologous End-Joining (NHEJ).
R-RNO-69473. G2/M DNA damage checkpoint.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase RNF8UniRule annotation (EC:6.3.2.-UniRule annotation)
Alternative name(s):
RING finger protein 8UniRule annotation
Gene namesi
Name:Rnf8UniRule annotation
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 20

Organism-specific databases

RGDi1308035. Rnf8.

Subcellular locationi

  • Nucleus UniRule annotation
  • Midbody UniRule annotation
  • Chromosometelomere UniRule annotation

  • Note: Recruited at uncapped telomeres. Following DNA double-strand breaks, recruited to the sites of damage. During prophase, concomitant with nuclear envelope breakdown, localizes throughout the cell, with a dotted pattern. In telophase, again in the nucleus and also with a discrete dotted pattern in the cytoplasm. In late telophase and during cytokinesis, localizes in the midbody of the tubulin bridge joining the daughter cells. Does not seem to be associated with condensed chromosomes at any time during the cell cycle.UniRule annotation

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Chromosome, Nucleus, Telomere

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003672771 – 487E3 ubiquitin-protein ligase RNF8Add BLAST487

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei157PhosphoserineBy similarity1

Post-translational modificationi

Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type polyubiquitination is also observed, but it doesn't require its own functional RING-type zinc finger.UniRule annotation

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ4KLN8.
PRIDEiQ4KLN8.

PTM databases

PhosphoSitePlusiQ4KLN8.

Expressioni

Gene expression databases

BgeeiENSRNOG00000047171.
ExpressionAtlasiQ4KLN8. baseline and differential.
GenevisibleiQ4KLN8. RN.

Interactioni

Subunit structurei

Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA domain) with phosphorylated HERC2 (via C-terminus).UniRule annotation

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000059852.

Structurei

3D structure databases

ProteinModelPortaliQ4KLN8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini38 – 92FHAUniRule annotationAdd BLAST55

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi298 – 347Gln-richAdd BLAST50

Domaini

The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and phosphorylated HERC2 (By similarity). This domain is also required for proper recruitment to DNA damage sites after UV irradiation, ionizing radiation, or treatment with an alkylating agent (By similarity).UniRule annotationBy similarity

Sequence similaritiesi

Belongs to the RNF8 family.UniRule annotation
Contains 1 FHA domain.UniRule annotation
Contains 1 RING-type zinc finger.UniRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri405 – 443RING-typeUniRule annotationAdd BLAST39

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410INBI. Eukaryota.
ENOG410Z9IW. LUCA.
GeneTreeiENSGT00400000022349.
HOGENOMiHOG000154169.
HOVERGENiHBG023954.
InParanoidiQ4KLN8.
KOiK10667.
OMAiIHKGDHI.

Family and domain databases

Gene3Di2.60.200.20. 1 hit.
3.30.40.10. 1 hit.
HAMAPiMF_03067. RNF8. 1 hit.
InterProiIPR000253. FHA_dom.
IPR017335. RNF8.
IPR008984. SMAD_FHA_domain.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00498. FHA. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]
PIRSFiPIRSF037950. E3_ubiquit_lig_RNF8. 1 hit.
SMARTiSM00240. FHA. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
PROSITEiPS50006. FHA_DOMAIN. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q4KLN8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGEPDPLVSG QLAARRSWCL RRLGMDREWL QLEAGSEVTI GRGFSVTYQL
60 70 80 90 100
ISKVCPLMIS RNHCVLKQNP EGQWTIMDNK SLNGVWLNRE RLAPLQGYCI
110 120 130 140 150
RKGDHIQLGV PLESKEHAEY EYEVIEEDRE SLAPCLAPKN DHTTEKHKGL
160 170 180 190 200
RTKRKFSSDG VESLPAEGPS DLRCPLAKGS SKPAEPEKLH GKGEAASQPL
210 220 230 240 250
GCLCPTLASL EASERTAGPH ACSTLPKVLE LYPKKQKACS PSASQSSLEL
260 270 280 290 300
FKMTMSRMLK LKTQMQEKQI AVLNVKRQAR KGSSKKVVRM EKELRDLQSQ
310 320 330 340 350
LYAEQAQQQA RVEQLEKTFQ EEEQHLQGLE KEQGECDLKQ QLLQALQEHR
360 370 380 390 400
ALMEELDRSK KDFEKIIQAK NKELERTKEE KDKVQAQKEE VLSHMNDVLE
410 420 430 440 450
NELQCIICSE YFIEAVTLNC AHSFCSFCIS EWMKRKVECP ICRKDIESRT
460 470 480
NSLVLDNCIS KMVERLSSDV KERRSVLIRE RRAKRLL
Length:487
Mass (Da):55,615
Last modified:August 2, 2005 - v1
Checksum:i7118C1ED670CB95C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC099079 mRNA. Translation: AAH99079.1.
RefSeqiNP_001020898.1. NM_001025727.1.
UniGeneiRn.12463.

Genome annotation databases

EnsembliENSRNOT00000065629; ENSRNOP00000059852; ENSRNOG00000047171.
GeneIDi361815.
KEGGirno:361815.
UCSCiRGD:1308035. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC099079 mRNA. Translation: AAH99079.1.
RefSeqiNP_001020898.1. NM_001025727.1.
UniGeneiRn.12463.

3D structure databases

ProteinModelPortaliQ4KLN8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000059852.

PTM databases

PhosphoSitePlusiQ4KLN8.

Proteomic databases

PaxDbiQ4KLN8.
PRIDEiQ4KLN8.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000065629; ENSRNOP00000059852; ENSRNOG00000047171.
GeneIDi361815.
KEGGirno:361815.
UCSCiRGD:1308035. rat.

Organism-specific databases

CTDi9025.
RGDi1308035. Rnf8.

Phylogenomic databases

eggNOGiENOG410INBI. Eukaryota.
ENOG410Z9IW. LUCA.
GeneTreeiENSGT00400000022349.
HOGENOMiHOG000154169.
HOVERGENiHBG023954.
InParanoidiQ4KLN8.
KOiK10667.
OMAiIHKGDHI.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiR-RNO-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-RNO-5693571. Nonhomologous End-Joining (NHEJ).
R-RNO-69473. G2/M DNA damage checkpoint.

Miscellaneous databases

PROiQ4KLN8.

Gene expression databases

BgeeiENSRNOG00000047171.
ExpressionAtlasiQ4KLN8. baseline and differential.
GenevisibleiQ4KLN8. RN.

Family and domain databases

Gene3Di2.60.200.20. 1 hit.
3.30.40.10. 1 hit.
HAMAPiMF_03067. RNF8. 1 hit.
InterProiIPR000253. FHA_dom.
IPR017335. RNF8.
IPR008984. SMAD_FHA_domain.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00498. FHA. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]
PIRSFiPIRSF037950. E3_ubiquit_lig_RNF8. 1 hit.
SMARTiSM00240. FHA. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
PROSITEiPS50006. FHA_DOMAIN. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRNF8_RAT
AccessioniPrimary (citable) accession number: Q4KLN8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 24, 2009
Last sequence update: August 2, 2005
Last modified: November 30, 2016
This is version 99 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

According to a well-established model, RNF8 initiate H2A 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to amplify H2A 'Lys-63'-linked ubiquitination. 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). 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. Additional evidences are however required to confirm these data.UniRule annotation

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. 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.