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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

RNF8 Gene

protein-coding GIFtS: 62
GCID: GC06P037321

ring finger protein 8, E3 ubiquitin protein ligase

(Previous names: ring finger protein (C3HC4 type) 8, ring finger protein...)

Explore 6 diseases affiliated with
RNF8 via

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(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, and/or ¹⁰fRNAdb)
About This Section

Aliases
Ring Finger Protein 8, E3 Ubiquitin Protein Ligase¹ ²		C3HC4-Type Zinc Finger Protein²
KIAA0646¹ ³ ⁵		E3 Ubiquitin-Protein Ligase RNF8²
Ring Finger Protein (C3HC4 Type) 8¹ ²		UBC13/UEV-Interacting Ring Finger Protein²
RING Finger Protein 8¹ ³		EC 6.3.2.-³
HRNF8¹		EC 6.3.2⁸

External Ids:	HGNC: 10071¹	Entrez Gene: 9025²	Ensembl: ENSG00000112130⁷	OMIM: 611685⁵	UniProtKB: O76064³

Export aliases for RNF8 gene to outside databases

Previous GC identifers: GC06P037324 GC06P037368 GC06P037429 GC06P037040

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for RNF8:

The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to

interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may

act as an ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. This protein is also known to play

a role in the DNA damage response and depletion of this protein causes cell growth inhibition and cell cycle arrest.

Alternative splicing results in multiple transcript variants. (provided by RefSeq, Feb 2012)

UniProtKB/Swiss-Prot: RNF8_HUMAN, O76064

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/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. 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

aggraving 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

Gene Wiki entry for RNF8

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section

RefSeq DNA sequence:

NC_000006.11 NC_018917.1 NT_007592.15

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the RNF8 gene promoter:
HFH-3 Pax-2 Pax-2a Nkx2-5 RORalpha1 FOXJ2 (long isoform) FOXO4 FOXJ2 MRF-2 Pax-4a
Other transcription factors

SwitchGear Promoter luciferase reporter plasmid: RNF8 promoter sequence

Search SABiosciences Chromatin IP Primers for RNF8

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat RNF8

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 6p21.3 Ensembl cytogenetic band: 6p21.2 HGNC cytogenetic band: 6p21.3

RNF8 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
RNF8 gene location

GeneLoc information about chromosome 6 GeneLoc Exon Structure

GeneLoc location for GC06P037321: view genomic region (about GC identifiers)

Start:	37,321,748 bp from pter	End:	37,362,514 bp from pter
Size:	40,767 bases	Orientation:	plus strand

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: RNF8_HUMAN, O76064 (See protein sequence)

Recommended Name: E3 ubiquitin-protein ligase RNF8

Size: 485 amino acids; 55518 Da

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 ATM-phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827' phosphorylated

HERC2 (via C-terminus). Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to

RNF8 degradation by the proteasome

Subcellular location: Nucleus. Midbody. Chromosome, telomere (By similarity). Note=Recruited at uncapped telomeres (By

similarity). 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

Developmental stage: Low levels at the G1-S boundary increase in intensity during S phase and until the end of the G2

phase. Abruptly decreases in late mitosis (at protein level). Barely detectable in anaphase

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 (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

Sequence caution: Sequence=BAA31621.2; Type=Erroneous initiation; Note=Translation N-terminally extended;

Sequence=BAG60572.1; Type=Erroneous translation; Note=Wrong choice of CDS; Sequence=EAX03945.1; Type=Erroneous gene

model prediction;

4 PDB 3D structures from and Proteopedia for RNF8:

2CSW (3D)

2PIE (3D)

4AYC (3D)

4EPO (3D)

Secondary accessions: A6NN24 A8MYC0 B4DPG0 Q53H16 Q5NKW5

Alternative splicing: 2 isoforms: O76064-1 O76064-2 (May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. No experimental confirmation available)

Explore the universe of human proteins at neXtProt for RNF8: NX_O76064

Post-translational modifications:

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 finger¹

View modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_O76064

4/5 DME Specific Peptides for RNF8 (O76064) (see all 5)

CPLMISR

RSWCLRR

DNKSLNGVW

IIQAKNKEL

RNF8 Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins (2 alternative transcripts):

NP_003949.1 NP_898901.1

ENSEMBL proteins:

ENSP00000362578 ENSP00000420268 ENSP00000229866 ENSP00000417736 ENSP00000419859

ENSP00000418879 ENSP00000417599 ENSP00000377961

Human Recombinant Protein Products:

	Browse Purified and Recombinant Proteins at EMD Millipore
	Browse R&D Systems for human recombinant proteins
	Browse recombinant and purified proteins available from Enzo Life Sciences
	Browse OriGene full length recombinant human proteins expressed in human HEK293 cells OriGene Protein Over-expression Lysate: RNF8 OriGene Custom Protein Services for RNF8
	GenScript Custom Purified and Recombinant Proteins Services for RNF8
	Novus Biologicals RNF8 Proteins Novus Biologicals RNF8 Lysates
	Browse Sino Biological Recombinant Proteins
	Browse ProSpec Recombinant Proteins
	Uscn Proteins for RNF8

Gene Ontology (GO): 5 cellular component terms (GO ID links to tree view): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0000151	ubiquitin ligase complex	IDA	18001825
GO:0000781	chromosome, telomeric region	ISS	--
GO:0005634	nucleus	IDA	18001825
GO:0030496	midbody	IEA	--
GO:0035861	site of double-strand break	IDA	--

RNF8 for ontologies About GeneDecksing

RNF8 Antibody Products:

	EMD Millipore Mono- and Polyclonal Antibodies for the study of RNF8
	R&D Systems Antibodies for RNF8
	OriGene Antibodies (see all 3): RNF8 OriGene Custom Antibody Services for RNF8
	GenScript Custom Superior Antibodies Services for RNF8
	Novus Biologicals RNF8 Antibodies
	Abcam antibodies for RNF8
	Uscn Antibodies for RNF8
	ThermoFisher Antibodies for RNF8

Assay Products for RNF8:

	Browse Kits and Assays available from EMD Millipore
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	Browse R&D Systems for biochemical assays
	GenScript Custom Assay Services for RNF8
	Browse Enzo Life Sciences for kits & assays
	Uscn ELISAs and CLIAs for RNF8

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

RNF8 for domains About GeneDecksing

5/6 InterPro domains/families (see all 6):

IPR017907 Znf_RING_CS

IPR008984 SMAD_FHA_domain

IPR001841 Znf_RING

IPR017335 E3_Ub_ligase_RNF8

IPR000253 FHA_dom

Graphical View of Domain Structure for InterPro Entry O76064

ProtoNet protein and cluster: O76064

1 Blocks protein family: IPB001841 Zn-finger

UniProtKB/Swiss-Prot: RNF8_HUMAN, O76064

Domain: The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2

Similarity: Belongs to the RNF8 family

Similarity: Contains 1 FHA domain

Similarity: Contains 1 RING-type zinc finger

(According to ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Function Summary: