A0A3Q1MQ87 · A0A3Q1MQ87_BOVIN

  • Protein
    E3 ubiquitin-protein ligase RNF8
  • Gene
    RNF8
  • Status
    UniProtKB unreviewed (TrEMBL)
  • Amino acids
  • Protein existence
    Inferred from homology
  • Annotation score
    5/5

Function

function

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. 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. 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.

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.

Catalytic activity

  • S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.
    EC:2.3.2.27 (UniProtKB | ENZYME | Rhea)

Pathway

Protein modification; protein ubiquitination.

GO annotations

AspectTerm
Cellular Componentchromosome, telomeric region
Cellular Componentcytoplasm
Cellular Componentmidbody
Cellular Componentnucleus
Cellular Componentubiquitin ligase complex
Molecular Functionchromatin binding
Molecular Functionhistone binding
Molecular Functionmetal ion binding
Molecular Functionubiquitin binding
Molecular Functionubiquitin-protein transferase activity
Biological Processcell division
Biological Processchromatin organization
Biological Processdouble-strand break repair
Biological Processpositive regulation of DNA repair
Biological Processprotein ubiquitination
Biological Processresponse to ionizing radiation

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    E3 ubiquitin-protein ligase RNF8
  • EC number
  • Alternative names
    • RING finger protein 8
    • RING-type E3 ubiquitin transferase RNF8

Gene names

    • Name
      RNF8

Organism names

  • Taxonomic identifier
  • Organism
  • Strain
    • Hereford
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Ruminantia > Pecora > Bovidae > Bovinae > Bos

Accessions

  • Primary accession
    A0A3Q1MQ87

Proteomes

Organism-specific databases

Subcellular Location

Nucleus
Cytoplasm
Midbody
Chromosome, telomere
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. During spermatogenesis, sequestered in the cytoplasm by PIWIL1: RNF8 is released following ubiquitination and degradation of PIWIL1.

Keywords

PTM/Processing

Post-translational modification

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.

Keywords

Expression

Gene expression databases

Interaction

Subunit

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). Interacts with PIWIL1; leading to sequester RNF8 in the cytoplasm.

Family & Domains

Features

Showing features for domain, region, compositional bias, coiled coil.

TypeIDPosition(s)Description
Domain38-92FHA
Region68-72Required for interaction with PIWIL1
Region143-176Disordered
Compositional bias144-161Basic and acidic residues
Region182-201Disordered
Coiled coil280-373
Domain384-422RING-type

Domain

The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and phosphorylated HERC2.

Sequence similarities

Belongs to the CHFR family.
Belongs to the RNF8 family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    466
  • Mass (Da)
    53,361
  • Last updated
    2019-04-10 v1
  • Checksum
    03982312696F834B
MGDPGSLVTEGRAGERSWCLRRVGMNTEWLLLEDGNEVTVGRGFGVTYQLVSKICPLMISRNHCILKQNAEGQWTIKDNKSLNGVWLNRERLEPLKVYSIHKGDHIQLGVPLENKENAEYEYEVTEEDWERIYPCLSPKSDQMMEKNKGLRTKRKFSLDELEGSGAEGPSNLKSKISKLSCEPGQQVKSHGKGKVASQPSEYLDPKLTSFEPSVKTTGAHVNPGPAKVIELLRKKKKASNPSASQSSLELFKVTMSRILMLKTQMQEKQVAVLNVKKQTKKGSSKKIVKMEQELQDLQSQLCAEQAQQQARVEQLEKTIQEEQQHLEYRSLVEELNRSKKNFEAIIQAKDKELEQTKEEKEKVQAQKEEVLSHMNDVLENELQCIICSEYFVEAVTLNCAHSFCSYCINEWMKRKVECPICRKDIKSKTRSLVLDNCISKMVDNLNSEVKERRIVLIRERKGKRLF

Computationally mapped potential isoform sequences

There are 7 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
Q2HJ46RNF8_BOVINRNF8487
A0A452DI91A0A452DI91_BOVINRNF8459
A0AAA9TBC7A0AAA9TBC7_BOVINRNF8465
A0AAA9U1E0A0AAA9U1E0_BOVINRNF8444
A0A3Q1MP84A0A3Q1MP84_BOVINRNF8504
A0A3Q1LPX0A0A3Q1LPX0_BOVINRNF8451
A0AAF7AKR0A0AAF7AKR0_BOVINRNF8490

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias144-161Basic and acidic residues

Keywords

Genome annotation databases

Similar Proteins

Disclaimer

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