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Protein

E3 ubiquitin-protein ligase RNF8

Gene

RNF8

Organism
Bos taurus (Bovine)
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. 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).By similarity

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
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)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri405 – 44339RING-typePROSITE-ProRule annotationAdd
BLAST

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

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase RNF8 (EC:6.3.2.-)
Alternative name(s):
RING finger protein 8
Gene namesi
Name:RNF8
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Chromosome 23

Subcellular locationi

  • Nucleus By similarity
  • Midbody By similarity
  • Chromosometelomere By similarity

  • 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 (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Chromosome, Nucleus, Telomere

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 487487E3 ubiquitin-protein ligase RNF8PRO_0000269199Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei157 – 1571PhosphoserineBy similarity

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 (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ2HJ46.
PRIDEiQ2HJ46.

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 ATM-phosphorylated MDC1. Interacts (via FHA domain) with phosphorylated HERC2 (via C-terminus) (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000010959.

Structurei

3D structure databases

ProteinModelPortaliQ2HJ46.
SMRiQ2HJ46. Positions 8-140.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini38 – 9255FHAPROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi292 – 34756Gln-richAdd
BLAST

Domaini

The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 as well as phosphorylated HERC2.By similarity

Sequence similaritiesi

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

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri405 – 44339RING-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410INBI. Eukaryota.
ENOG410Z9IW. LUCA.
GeneTreeiENSGT00400000022349.
HOGENOMiHOG000154169.
HOVERGENiHBG023954.
InParanoidiQ2HJ46.
KOiK10667.
OMAiIHKGDHI.
OrthoDBiEOG75J0N0.
TreeFamiTF330957.

Family and domain databases

Gene3Di2.60.200.20. 1 hit.
3.30.40.10. 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.

Q2HJ46-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGDPGSLVTE GRAGERSWCL RRVGMNTEWL LLEDGNEVTV GRGFGVTYQL
60 70 80 90 100
VSKICPLMIS RNHCILKQNA EGQWTIKDNK SLNGVWLNRE RLEPLKVYSI
110 120 130 140 150
HKGDHIQLGV PLENKENAEY EYEVTEEDWE RIYPCLSPKS DQMMEKNKGL
160 170 180 190 200
RTKRKFSLDE LEGSGAEGPS NLKSKISKLS CEPGQQVKSH GKGKVASQPS
210 220 230 240 250
EYLDPKLTSF EPSVKTTGAH VNPGPAKVIE LLRKKKKASN PSASQSSLEL
260 270 280 290 300
FKVTMSRILM LKTQMQEKQV AVLNVKKQTK KGSSKKIVKM EQELQDLQSQ
310 320 330 340 350
LCAEQAQQQA RVEQLEKTIQ EEQQHLEGLE KEEGEEDLKQ QLAQALQEYR
360 370 380 390 400
SLVEELNRSK KNFEAIIQAK DKELEQTKEE KEKVQAQKEE VLSHMNDVLE
410 420 430 440 450
NELQCIICSE YFVEAVTLNC AHSFCSYCIN EWMKRKVECP ICRKDIKSKT
460 470 480
RSLVLDNCIS KMVDNLNSEV KERRIVLIRE RKGKRLF
Length:487
Mass (Da):55,729
Last modified:March 21, 2006 - v1
Checksum:iB9AD27A964F9F112
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC113317 mRNA. Translation: AAI13318.1.
RefSeqiNP_001039681.1. NM_001046216.1.
UniGeneiBt.41339.

Genome annotation databases

EnsembliENSBTAT00000010959; ENSBTAP00000010959; ENSBTAG00000008321.
GeneIDi515933.
KEGGibta:515933.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC113317 mRNA. Translation: AAI13318.1.
RefSeqiNP_001039681.1. NM_001046216.1.
UniGeneiBt.41339.

3D structure databases

ProteinModelPortaliQ2HJ46.
SMRiQ2HJ46. Positions 8-140.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000010959.

Proteomic databases

PaxDbiQ2HJ46.
PRIDEiQ2HJ46.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSBTAT00000010959; ENSBTAP00000010959; ENSBTAG00000008321.
GeneIDi515933.
KEGGibta:515933.

Organism-specific databases

CTDi9025.

Phylogenomic databases

eggNOGiENOG410INBI. Eukaryota.
ENOG410Z9IW. LUCA.
GeneTreeiENSGT00400000022349.
HOGENOMiHOG000154169.
HOVERGENiHBG023954.
InParanoidiQ2HJ46.
KOiK10667.
OMAiIHKGDHI.
OrthoDBiEOG75J0N0.
TreeFamiTF330957.

Enzyme and pathway databases

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

Family and domain databases

Gene3Di2.60.200.20. 1 hit.
3.30.40.10. 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...

Publicationsi

  1. NIH - Mammalian Gene Collection (MGC) project
    Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: Hereford.
    Tissue: Uterus.

Entry informationi

Entry nameiRNF8_BOVIN
AccessioniPrimary (citable) accession number: Q2HJ46
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 12, 2006
Last sequence update: March 21, 2006
Last modified: June 8, 2016
This is version 85 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.Curated

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.