Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q8VC56 (RNF8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase RNF8

EC=6.3.2.-
Alternative name(s):
ActA-interacting protein 37
Short name=AIP37
LaXp180
RING finger protein 8
Gene names
Name:Rnf8
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length488 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. 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. Ref.5 Ref.6 Ref.7 Ref.8 Ref.10

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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 'Thr-4829' phosphorylated HERC2 (via C-terminus) By similarity. May interact with the L.monocytogenes protein actA; however, given these errors in the sequence (AJ242721), the relevance of the interaction with actA remains to be confirmed. Ref.4

Subcellular location

Nucleus By similarity. Midbody By similarity. Chromosometelomere. Note: 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. Recruited at uncapped telomeres. Ref.8 Ref.9

Domain

The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and 'Thr-4829' phosphorylated HERC2 By similarity.

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 By similarity.

Disruption phenotype

Male mice are infertile, while females do not show defects. Male mice display defects in histone H2A and H2B ubiquitination in testis cells. While meiotic sex chromosome inactivation in the XY body prior to meiosis is not affected, H4K16ac is decreased, leading to defects in the replacement of histones by protamines during spermiogenesis. Mice lacking both Rnf8 and Chfr develop thymic lymphomas and chromosomes are frequently altered, due to defects in DNA damage response and defects in damage-induced activation of ATM kinase. Ref.5 Ref.7

Sequence similarities

Belongs to the RNF8 family.

Contains 1 FHA domain.

Contains 1 RING-type zinc finger.

Caution

The precise role of Rnf8 at telomeres is subject to debate. 2 publications reported recruitment of Rnf8 at uncapped telomeres followed by regulation of non-homologous end joining (NHEJ), however the 2 publications reported different data and conclusions. According to a report, Rnf8 promotes telomere end protection and inhibits NHEJ by mediating ubiquitination via 'Lys-63'-linked ubiquitin and stabilization of Tpp1 at uncapped telomeres (Ref.9). According to another report, Rnf8 recruitment at uncapped telomeres leads to promote NHEJ and the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that Rnf8 may have a detrimental role in case of telomeric crisis and enhance cancer development by aggravating telomere-induced genome instability (Ref.8).

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.

Sequence caution

The sequence CAB92239.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

The sequence CAB92239.1 differs from that shown. Reason: Frameshift at positions 219, 266 and 283.

Ontologies

Keywords
   Biological processCell cycle
Cell division
DNA damage
DNA repair
Mitosis
Ubl conjugation pathway
   Cellular componentChromosome
Nucleus
Telomere
   DomainZinc-finger
   LigandMetal-binding
Zinc
   Molecular functionChromatin regulator
Ligase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to DNA damage stimulus

Inferred from direct assay Ref.8. Source: UniProtKB

double-strand break repair

Inferred from sequence or structural similarity. Source: UniProtKB

double-strand break repair via nonhomologous end joining

Inferred from mutant phenotype Ref.8Ref.10. Source: UniProtKB

histone H2A K63-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

histone H2A ubiquitination

Inferred from mutant phenotype PubMed 19015238Ref.5. Source: UniProtKB

histone H2B ubiquitination

Inferred from mutant phenotype PubMed 19015238Ref.5. Source: UniProtKB

histone exchange

Inferred from mutant phenotype Ref.5. Source: UniProtKB

isotype switching

Inferred from mutant phenotype Ref.6. Source: UniProtKB

mitotic nuclear division

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of translational elongation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of DNA repair

Inferred from sequence or structural similarity. Source: UniProtKB

protein K48-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein K63-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

response to ionizing radiation

Inferred from sequence or structural similarity. Source: UniProtKB

spermatid development

Inferred from mutant phenotype Ref.5. Source: UniProtKB

ubiquitin-dependent protein catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentchromosome, telomeric region

Inferred from direct assay Ref.8. Source: UniProtKB

midbody

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

site of double-strand break

Inferred from sequence or structural similarity. Source: UniProtKB

ubiquitin ligase complex

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionchromatin binding

Inferred from sequence or structural similarity. Source: UniProtKB

histone binding

Inferred from mutant phenotype PubMed 19015238. Source: UniProtKB

protein homodimerization activity

Inferred from sequence or structural similarity. Source: UniProtKB

ubiquitin-protein transferase activity

Inferred from mutant phenotype PubMed 19015238. Source: UniProtKB

zinc ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 488488E3 ubiquitin-protein ligase RNF8
PRO_0000056049

Regions

Domain38 – 9255FHA
Zinc finger406 – 44439RING-type
Compositional bias299 – 35153Gln-rich

Amino acid modifications

Modified residue1571Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
Q8VC56 [UniParc].

Last modified March 1, 2002. Version 1.
Checksum: 428242204EBC44A1

FASTA48855,517
        10         20         30         40         50         60 
MGEPDPLVSG QLAARRSWCL RRLGMDCEWL QLEAGTEVTI GRGLSVTYQL ISKVCPLMIS 

        70         80         90        100        110        120 
RSHCVLKQNP EGQWTIMDNK SLNGVWLNRE RLAPLQGYCI RKGDHIQLGV PLESRETAEY 

       130        140        150        160        170        180 
EYEVIEEDWE SLAPCLAPKN DQRMEKHKGS RTKRKFSSPG LENLPAEGSS DLRCPLANVA 

       190        200        210        220        230        240 
SKPIEPEKLH GKGDASSQSL GCLCPGLTSL KASERAAGPH ACSALPKVLE LSCPKKQKAC 

       250        260        270        280        290        300 
RPSASQNSLE LFKVTMSRML KLKTQMQEKQ IAVLNVKRQT RKGSSKKIVR MEKELRNLQS 

       310        320        330        340        350        360 
QLYAEQAQQQ ARVEQLEKTF QEEAHYLQGL EKEQGECDLK QQLVQALQEH QALMEELNCS 

       370        380        390        400        410        420 
KKDFEKIIQA KNKELEQTKE EKDKVQAQKE EVLSHMNDLL ENELQCIICS EYFIEAVTLN 

       430        440        450        460        470        480 
CAHSFCSFCI NEWMKRKVEC PICRKDIESR TNSLVLDNCI SKMVDNLSSD VKERRSVLIR 


ERRAKRLS 

« Hide

References

« Hide 'large scale' references
[1]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J.
Tissue: Extraembryonic tissue, Liver and Placenta.
[2]"Cloning of mouse full open reading frames in Gateway(R) system entry vector (pDONR201)."
Ebert L., Muenstermann E., Schatten R., Henze S., Bohn E., Mollenhauer J., Wiemann S., Schick M., Korn B.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Kidney.
[4]"LaXp180, a mammalian ActA-binding protein, identified with the yeast two-hybrid system co-localizes with intracellular Listeria monocytogenes."
Pfeuffer T., Goebel W., Laubinger J., Bachmann M., Kuhn M.
Cell. Microbiol. 2:101-114(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-283, INTERACTION WITH ACTA.
Strain: CD-1.
Tissue: Embryo.
[5]"RNF8-dependent histone modifications regulate nucleosome removal during spermatogenesis."
Lu L.Y., Wu J., Ye L., Gavrilina G.B., Saunders T.L., Yu X.
Dev. Cell 18:371-384(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]"The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination."
Ramachandran S., Chahwan R., Nepal R.M., Frieder D., Panier S., Roa S., Zaheen A., Durocher D., Scharff M.D., Martin A.
Proc. Natl. Acad. Sci. U.S.A. 107:809-814(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"Chfr and RNF8 synergistically regulate ATM activation."
Wu J., Chen Y., Lu L.Y., Wu Y., Paulsen M.T., Ljungman M., Ferguson D.O., Yu X.
Nat. Struct. Mol. Biol. 18:761-768(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[8]"DNA-damage response and repair activities at uncapped telomeres depend on RNF8."
Peuscher M.H., Jacobs J.J.
Nat. Cell Biol. 13:1139-1145(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]"The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection."
Rai R., Li J.M., Zheng H., Lok G.T., Deng Y., Huen M.S., Chen J., Jin J., Chang S.
Nat. Struct. Mol. Biol. 18:1400-1407(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[10]"The E3 ligase RNF8 regulates KU80 removal and NHEJ repair."
Feng L., Chen J.
Nat. Struct. Mol. Biol. 19:201-206(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK076180 mRNA. Translation: BAC36236.1.
AK147168 mRNA. Translation: BAE27732.1.
CT010295 mRNA. Translation: CAJ18503.1.
BC021778 mRNA. Translation: AAH21778.1.
AJ242721 mRNA. Translation: CAB92239.1. Frameshift.
CCDSCCDS37538.1.
RefSeqNP_067394.1. NM_021419.1.
UniGeneMm.305994.

3D structure databases

ProteinModelPortalQ8VC56.
SMRQ8VC56. Positions 8-140, 348-486.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid208404. 1 interaction.
DIPDIP-59448N.

PTM databases

PhosphoSiteQ8VC56.

Proteomic databases

PRIDEQ8VC56.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000024817; ENSMUSP00000024817; ENSMUSG00000090083.
GeneID58230.
KEGGmmu:58230.
UCSCuc008btf.1. mouse.

Organism-specific databases

CTD9025.
MGIMGI:1929069. Rnf8.

Phylogenomic databases

GeneTreeENSGT00400000022349.
HOGENOMHOG000154169.
HOVERGENHBG023954.
KOK10667.
TreeFamTF330957.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

BgeeQ8VC56.
CleanExMM_RNF8.
GenevestigatorQ8VC56.

Family and domain databases

Gene3D2.60.200.20. 1 hit.
3.30.40.10. 1 hit.
InterProIPR017335. E3_Ub_ligase_RNF8.
IPR000253. FHA_dom.
IPR008984. SMAD_FHA_domain.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamPF00498. FHA. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]
PIRSFPIRSF037950. E3_ubiquit_lig_RNF8. 1 hit.
SMARTSM00240. FHA. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]
SUPFAMSSF49879. SSF49879. 1 hit.
PROSITEPS50006. FHA_DOMAIN. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio314253.
PROQ8VC56.
SOURCESearch...

Entry information

Entry nameRNF8_MOUSE
AccessionPrimary (citable) accession number: Q8VC56
Secondary accession number(s): Q4FJV7, Q9JK13
Entry history
Integrated into UniProtKB/Swiss-Prot: June 6, 2002
Last sequence update: March 1, 2002
Last modified: July 9, 2014
This is version 104 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot