RNF8

Summary

RNF8 (ring finger protein 8, HGNC:10071) is a protein-coding gene on chromosome 6p21.2, encoding E3 ubiquitin-protein ligase RNF8 (O76064). 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 ‘…. It is a selective cancer dependency (DepMap: 46.5% of cell lines).

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.

Source: NCBI Gene 9025 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 23 total
• Cancer dependency (DepMap): dependent in 46.5% of screened cell lines
• MANE Select transcript: NM_003958

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10071
Approved symbol	RNF8
Name	ring finger protein 8
Location	6p21.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0646
Ensembl gene	ENSG00000112130
Ensembl biotype	protein_coding
OMIM	611685
Entrez	9025

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000229866, ENST00000373479, ENST00000469316, ENST00000469731, ENST00000479516, ENST00000487950, ENST00000494320, ENST00000498460, ENST00000854574, ENST00000854575, ENST00000854576, ENST00000854577, ENST00000918865, ENST00000918866, ENST00000918867, ENST00000918868, ENST00000952611, ENST00000952612, ENST00000952613

RefSeq mRNA: 2 — MANE Select: NM_003958 NM_003958, NM_183078

CCDS: CCDS4833, CCDS4834

Canonical transcript exons

ENST00000373479 — 8 exons

Exon	Start	End
ENSE00001556351	37353983	37354275
ENSE00001884472	37390742	37394734
ENSE00003467156	37371512	37371574
ENSE00003497068	37381150	37381354
ENSE00003542298	37368484	37369218
ENSE00003636217	37374620	37374709
ENSE00003642033	37360446	37360574
ENSE00003669774	37376926	37377033

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 89.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6123 / max 172.4219, expressed in 1796 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67631	11.6118	1760
67632	7.0005	1664

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	89.45	gold quality
ganglionic eminence	UBERON:0004023	88.87	gold quality
cerebellar hemisphere	UBERON:0002245	88.17	gold quality
cerebellar cortex	UBERON:0002129	88.12	gold quality
left testis	UBERON:0004533	87.90	gold quality
right testis	UBERON:0004534	87.89	gold quality
ventricular zone	UBERON:0003053	87.74	gold quality
islet of Langerhans	UBERON:0000006	87.66	gold quality
prefrontal cortex	UBERON:0000451	87.61	gold quality
cerebellum	UBERON:0002037	87.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.53	gold quality
testis	UBERON:0000473	87.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.28	gold quality
esophagus mucosa	UBERON:0002469	87.14	gold quality
right frontal lobe	UBERON:0002810	87.02	gold quality
anterior cingulate cortex	UBERON:0009835	86.80	gold quality
cingulate cortex	UBERON:0003027	86.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.32	gold quality
right atrium auricular region	UBERON:0006631	86.19	gold quality
neocortex	UBERON:0001950	86.03	gold quality
embryo	UBERON:0000922	86.02	gold quality
frontal cortex	UBERON:0001870	86.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.97	gold quality
lower esophagus mucosa	UBERON:0035834	85.81	gold quality
endometrium	UBERON:0001295	85.78	gold quality
gastrocnemius	UBERON:0001388	85.72	gold quality
apex of heart	UBERON:0002098	85.68	gold quality
descending thoracic aorta	UBERON:0002345	85.65	gold quality
right adrenal gland cortex	UBERON:0035827	85.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CHD4

miRNA regulators (miRDB)

162 targeting RNF8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 46.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• results suggest a novel function of RNF8 as a regulator of RXR alpha-mediated transcriptional activity through interaction between their respective N-terminal regions (PMID:14981089)
• Regulates the rate of exit from mitosis and cytokinesis. (PMID:17724460)
• RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. (PMID:18001824)
• RNF8 is a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress. (PMID:18001825)
• results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination (PMID:18006705)
• the human Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage (PMID:18077395)
• RNF8 is the human orthologue of the yeast protein Dma1p (PMID:18171988)
• RNF8 ubiquitylation pathways are essential for 53BP1 regulation in response to ionizing radiation, whereas RNF8-independent pathways contribute to 53BP1 targeting and phosphorylation in response to UV light and other forms of DNA replication stress (PMID:18337245)
• Depletion of RAP80 or RNF8 impairs the translocation of BRCA1 to DNA damage sites and results in defective cell cycle checkpoint control and DSB repair (PMID:18550271)
• RNF8 readily mono-ubiquitinates PCNA in the presence of UbcH5c, and polyubiquitinates PCNA in the added presence of Ubc13/Uev1a. (PMID:18948756)
• subset of PTIP.PA1 complex is recruited to DNA damage sites via the RNF8-dependent pathway and is required for cell survival in response to DNA damage. (PMID:19124460)
• Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. (PMID:19797077)
• Data identify RNF8 and RNF168, cellular histone ubiquitin ligases responsible for anchoring repair factors at sites of damage, as new targets for ICP0-mediated degradation. (PMID:20075863)
• Ubiquitin ligase does not protect cells from Nutlin-3-mediated apoptosis, indicating that RNF8 does not regulate 53BP1 protein. (PMID:20080757)
• Data show that the ATM signalling mediator proteins MDC1, RNF8, RNF168 and 53BP1 are also required for heterochromatic DSB repair. (PMID:20081839)
• Phosphorylated NPM1 may interact with RNF8-dependent ubiquitin conjugates at sites of DNA damage. (PMID:20713529)
• The E3 Ubiquitin ligases, RNF8 and RNF168, are recruited to DNA damage foci in late mitosis, presumably to prime sites for the DNA damage response, 53BP1, recruitment in early G1. (PMID:21412056)
• the differential requirement for the ubiquitin ligase RNF8 in facilitating repair of replication stress-associated DNA damage (PMID:21558560)
• These results suggest that RNF8 is downregulated in many cancer cells and inversely correlated with Plk1. (PMID:21635870)
• Studies indicate that Non-proteolytic ubiquitylation of chromatin surrounding DSBs, mediated by the RNF8/RNF168 ubiquitin ligase cascade, has emerged as a key mechanism for restoration of genome integrity. (PMID:21664912)
• The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. (PMID:21698222)
• entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families (PMID:21774837)
• Data show that depletion of RNF8, as well as of the E3 ligase RNF168, reduces telomere-induced genome instability. (PMID:21857671)
• The authors find that RNF8 regulates the abundance of the nonhomologous end-joining (NHEJ) repair protein KU80 at sites of DNA damage. (PMID:22266820)
• The authors propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites. (PMID:22373579)
• By mimicking a cellular phosphosite, ICP0 binds RNF8 via the RNF8 forkhead associated (FHA) domain. Phosphorylation of ICP0 T67 by CK1 recruits RNF8 for degradation and thereby promotes viral transcription (PMID:22405594)
• In response to double-strand breaks, both HERC2 and RNF168 were specifically modified with SUMO1 at double-strand break sites in a manner dependent on the SUMO E3 ligase PIAS4. (PMID:22508508)
• A new mechanism of chromatin remodelling-assisted ubiquitylation was shown, which involves cooperation between CHD4 and RNF8 to create a local chromatin environment permissive to the assembly of checkpoint and repair machineries at DNA lesions. (PMID:22531782)
• Data show RING finger (RNF) E3 ubiquitin ligase RNF8 dimerizes and binds to E2 ubiquitin-conjugating complex Ubc13/Mms2 with formation of Lys-63 ubiquitin chains, whereas the RNF168 RING domain is a monomer and does not catalyze Lys-6 ubiquitylation. (PMID:22589545)
• Data indicate that RNF8 and FAAP20 (C1orf86) are needed for efficient Fanconi anemia group D2 protein FANCD2 monoubiquitination. (PMID:22705371)
• RNF8 may play a role in protein synthesis, possibly linking the nucleolar exit of this factor to the attenuation of protein synthesis in response to DNA damage. (PMID:22814251)
• Data indicate that RNF8-dependent chromatin ubiquitination is required for RAD51 assembly in BRCA1/53BP1-depleted cells. (PMID:22865450)
• PALB2 localization depends on the presence of MDC1, RNF8, RAP80 and Abraxas upstream of BRCA1. (PMID:23038782)
• Nbs1 is one important target of RNF8 to regulate DNA DSB repair. (PMID:23115235)
• The PARP1-dependent localization of BAL1-BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1, and RNF8. (PMID:23230272)
• The identification of RNF8 allows new insights into the integration of the control of p12 degradation by different DNA damage signaling pathways. (PMID:23233665)
• RNF8 maintains genome stability through independent, yet analogous, nuclear and cytoplasmic ubiquitylation activities (PMID:23442799)
• findings implicate USP44 in negative regulation of the RNF8/RNF168 pathway (PMID:23615962)
• Finding that RNF8 is less abundant than RNF168 identifies RNF8 as a rate-limiting determinant of focal repair complex assembly. (PMID:25304081)
• Depletion of RNF8 or RNF168 blocks the degradation of diffusely localized nuclear 53BP1. (PMID:25337968)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf8	ENSDARG00000044949
mus_musculus	Rnf8	ENSMUSG00000090083

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF8 — O76064 (reviewed: O76064)

Alternative names: RING finger protein 8, RING-type E3 ubiquitin transferase RNF8

All UniProt accessions (5): C9J858, O76064, F8WDH8, F8WEW6, H7C4L7

UniProt curated annotations — full annotation on UniProt →

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. Promotes the recruitment of NBN to DNA damage sites by catalyzing ‘Lys-6’-linked ubiquitination of NBN. 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. 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.

Subunit / interactions. 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 with PIWIL1; leading to sequester RNF8 in the cytoplasm. Interacts with WRAP53/TCAB1. (Microbial infection) Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8 degradation by the proteasome.

Subcellular location. Nucleus. Cytoplasm. Midbody. Chromosome. Telomere.

Tissue specificity. Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells.

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 finger.

Domain organisation. The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and ‘Thr-4827’ phosphorylated HERC2. This domain is required for proper recruitment to DNA damage sites after UV irradiation, ionizing radiation, or treatment with an alkylating agent.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the RNF8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O76064-1	1	yes
O76064-2	2
O76064-3	3

RefSeq proteins (2): NP_003949, NP_898901 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR001841	Znf_RING	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017335	RNF8	Family
IPR017907	Znf_RING_CS	Conserved_site

Pfam: PF00498, PF13920

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (40 total): strand 11, helix 7, mutagenesis site 5, splice variant 4, turn 3, sequence variant 2, sequence conflict 2, region of interest 2, chain 1, domain 1, zinc finger region 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2PIE	X-RAY DIFFRACTION	1.35
4AYC	X-RAY DIFFRACTION	1.9
4ORH	X-RAY DIFFRACTION	4.8
4WHV	X-RAY DIFFRACTION	8.3
2CSW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O76064-F1	76.43	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 157

Mutagenesis-validated functional residues (5):

Position	Phenotype
42	abolishes interaction with atm-phosphorylated mdc1. abolishes interaction with human herpesvirus 1 icp0. abolishes recru
403	marked reduction of e2-dependent ubiquitination of histone h2a. loss of ube2e2- and ube2n-binding. loss of nuclear local
405	impairs interaction with ube2l6/ubch8 and ability to mediate ’lys-48’-linked ubiquitination e3 ligase activity, while it
406	abolishes ubiquitin-ligase activity.
443	does not affect the monomeric structure but abolishes ability to monoubiquitinate h2a in nucleosomes.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-1640170	Cell Cycle
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-5693606	DNA Double Strand Break Response
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73894	DNA Repair

MSigDB gene sets: 196 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_B_CELL_ACTIVATION, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_IMMUNOGLOBULIN_PRODUCTION

GO Biological Process (23): double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), ubiquitin-dependent protein catabolic process (GO:0006511), DNA damage response (GO:0006974), response to ionizing radiation (GO:0010212), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), sperm DNA condensation (GO:0035092), interstrand cross-link repair (GO:0036297), epigenetic regulation of gene expression (GO:0040029), signal transduction in response to DNA damage (GO:0042770), isotype switching (GO:0045190), positive regulation of DNA repair (GO:0045739), cell division (GO:0051301), protein autoubiquitination (GO:0051865), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), protein K6-linked ubiquitination (GO:0085020), DNA repair-dependent chromatin remodeling (GO:0140861), positive regulation of double-strand break repair via homologous recombination (GO:1905168), DNA repair (GO:0006281), chromatin organization (GO:0006325), protein ubiquitination (GO:0016567), protein localization to site of double-strand break (GO:1990166)

GO Molecular Function (12): chromatin binding (GO:0003682), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), histone binding (GO:0042393), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ubiquitin binding (GO:0043130), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (9): ubiquitin ligase complex (GO:0000151), chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), midbody (GO:0030496), site of double-strand break (GO:0035861), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
DNA Double-Strand Break Repair	3
DNA Double Strand Break Response	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1
DNA Repair	1
Homology Directed Repair	1
Cell Cycle Checkpoints	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA repair	3
DNA damage response	3
protein polyubiquitination	3
protein ubiquitination	2
chromatin remodeling	2
binding	2
protein binding	2
double-strand break repair	1
modification-dependent protein catabolic process	1
cellular response to stress	1
response to radiation	1
transcription elongation by RNA polymerase II	1
negative regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
chromatin organization	1
spermatid nucleus differentiation	1
regulation of gene expression	1
intracellular signal transduction	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
cellular process	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
DNA metabolic process	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
identical protein binding	1
protein dimerization activity	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

2736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF8	MDC1	Q14676	999
RNF8	UBE2N	P61088	997
RNF8	RNF168	Q8IYW5	996
RNF8	TP53BP1	Q12888	984
RNF8	UIMC1	Q96RL1	946
RNF8	BRCA1	P38398	931
RNF8	H2AX	P16104	898
RNF8	CHD4	Q14839	866
RNF8	H2AC20	Q16777	855
RNF8	H2AC19	P20670	855
RNF8	ATM	Q13315	833
RNF8	PIAS4	Q8N2W9	823
RNF8	BRCC3	P46736	780
RNF8	OTUB1	Q96FW1	754
RNF8	BARD1	Q99728	750

IntAct

237 interactions, top by confidence:

A	B	Type	Score
WASL	RNF8	psi-mi:“MI:0915”(physical association)	0.830
RNF8	TMEM79	psi-mi:“MI:0915”(physical association)	0.780
RNF8	SEPTIN3	psi-mi:“MI:0915”(physical association)	0.780
PNMA2	RNF8	psi-mi:“MI:0915”(physical association)	0.780
RNF8	MAD1L1	psi-mi:“MI:0915”(physical association)	0.780
SEPTIN3	RNF8	psi-mi:“MI:0915”(physical association)	0.780
TMEM79	RNF8	psi-mi:“MI:0915”(physical association)	0.780
MAD1L1	RNF8	psi-mi:“MI:0915”(physical association)	0.780
RNF8	PNMA2	psi-mi:“MI:0915”(physical association)	0.780
RNF8	MDC1	psi-mi:“MI:0915”(physical association)	0.720
MDC1	RNF8	psi-mi:“MI:0915”(physical association)	0.720
MDC1	RNF8	psi-mi:“MI:0403”(colocalization)	0.720

BioGRID (595): HERC2 (Affinity Capture-Western), USP16 (Affinity Capture-Western), RNF8 (Affinity Capture-Western), RNF8 (Two-hybrid), RNF8 (Two-hybrid), RNF8 (Two-hybrid), PNMA2 (Two-hybrid), RBFOX2 (Two-hybrid), SEPT3 (Two-hybrid), HOMEZ (Two-hybrid), TMEM79 (Two-hybrid), UBC (Biochemical Activity), BLM (Reconstituted Complex), UBC (Biochemical Activity), UBE2N (Reconstituted Complex)

ESM2 similar proteins: D3ZSP7, E9QHE3, F1M649, F1MHT9, F6ZQ54, O16616, O60858, O76064, O88196, O95361, P36406, P36407, Q07DV3, Q13075, Q13129, Q14258, Q309B1, Q32L60, Q38HM4, Q3UP24, Q4VSN4, Q4VSN5, Q503I2, Q5M7V1, Q5R4I2, Q5R760, Q5RB52, Q5ZMD4, Q61510, Q6NRG0, Q6XUX3, Q803C1, Q8BGX0, Q8IWR1, Q8IWZ5, Q8R2Q0, Q8TDY2, Q8WXH0, Q922Y2, Q969Q1

Diamond homologs: A0A1L8FG46, A0A1L8FM16, B1AUE5, E7FDW2, O35445, O60683, O64425, O76064, P09309, P68907, P87176, Q09463, Q2HJ46, Q4KLN8, Q54S31, Q568Y3, Q5M807, Q5R4I2, Q5RFK9, Q5ZIR9, Q69ZS0, Q6PC78, Q803C1, Q80Z37, Q8HXW8, Q8VC56, Q91YT2, Q96GF1, Q99942, Q9NS56, Q9P3U8, Q9SYU4, Q9UPQ7, Q9UUF0, Q9V8P9, A0A3B3IT33, A6NCK2, A6NDI0, A6NGJ6, A6NI03

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
RNF8	up-regulates	H2AX	ubiquitination
RNF8	up-regulates	H2AC11	ubiquitination
MDC1	up-regulates	RNF8	relocalization
RNF8	up-regulates	UBE2N	binding
RNF8	up-regulates	RAD18	binding
RNF8	up-regulates	“Histone H2A”	ubiquitination
RNF8	“up-regulates activity”	L3MBTL2	ubiquitination
RNF8	up-regulates	DNA_repair
Ub:E2	“up-regulates activity”	RNF8	ubiquitination
RNF8	“up-regulates activity”	BLM	ubiquitination
RNF8	“up-regulates quantity by stabilization”	ACD	polyubiquitination
RNF8	down-regulates	H1-2	polyubiquitination
RNF8	“up-regulates activity”	XRN2	ubiquitination
RNF8	“up-regulates activity”	TPP1	ubiquitination
RNF8	“up-regulates quantity by stabilization”	BCL10	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nonhomologous End-Joining (NHEJ)	8	39.5×	8e-09
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	7	30.1×	6e-07
G2/M DNA damage checkpoint	7	24.8×	2e-06
Processing of DNA double-strand break ends	7	23.5×	2e-06
G2/M Checkpoints	5	19.8×	3e-04
DNA Repair	5	14.5×	7e-04
Cell Cycle Checkpoints	5	13.0×	9e-04
Cell Cycle	7	7.4×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair	6	23.0×	5e-05
double-strand break repair via homologous recombination	5	14.7×	1e-03
DNA damage response	9	9.1×	8e-05
protein phosphorylation	7	9.0×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

23 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1558 predictions. Top by Δscore:

Variant	Effect	Δscore
6:37371571:GGAG:G	donor_gain	1.0000
6:37371572:GAGG:G	donor_gain	1.0000
6:37374614:TTGCA:T	acceptor_loss	1.0000
6:37374615:TGCA:T	acceptor_loss	1.0000
6:37374616:GCAG:G	acceptor_loss	1.0000
6:37374617:CA:C	acceptor_loss	1.0000
6:37374618:A:AG	acceptor_gain	1.0000
6:37374618:AG:A	acceptor_loss	1.0000
6:37374619:G:GG	acceptor_gain	1.0000
6:37374619:GC:G	acceptor_gain	1.0000
6:37374619:GCAT:G	acceptor_gain	1.0000
6:37374619:GCATT:G	acceptor_gain	1.0000
6:37354261:G:GT	donor_gain	0.9900
6:37360442:CCAG:C	acceptor_loss	0.9900
6:37360443:CAGGT:C	acceptor_loss	0.9900
6:37360444:A:T	acceptor_loss	0.9900
6:37360445:G:GA	acceptor_loss	0.9900
6:37368483:GA:G	acceptor_gain	0.9900
6:37369234:G:T	donor_gain	0.9900
6:37371510:AG:A	acceptor_gain	0.9900
6:37371511:GG:G	acceptor_gain	0.9900
6:37371570:AGGAG:A	donor_loss	0.9900
6:37371572:GAGGT:G	donor_loss	0.9900
6:37371573:AGG:A	donor_loss	0.9900
6:37371574:G:GT	donor_loss	0.9900
6:37371575:GT:G	donor_loss	0.9900
6:37371576:T:G	donor_loss	0.9900
6:37374619:GCA:G	acceptor_gain	0.9900
6:37374706:CAAG:C	donor_loss	0.9900
6:37374708:AGGT:A	donor_loss	0.9900

AlphaMissense

3213 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:37377004:T:C	C403R	0.999
6:37381177:T:C	F422L	0.998
6:37381179:C:A	F422L	0.998
6:37381179:C:G	F422L	0.998
6:37381180:T:C	C423R	0.998
6:37381222:T:C	C437R	0.998
6:37377013:T:C	C406R	0.997
6:37381182:C:G	C423W	0.997
6:37381191:T:G	C426W	0.997
6:37376999:T:C	L401P	0.996
6:37377004:T:A	C403S	0.996
6:37377005:G:C	C403S	0.996
6:37377015:T:G	C406W	0.996
6:37381189:T:C	C426R	0.996
6:37381201:T:A	W430R	0.996
6:37381201:T:C	W430R	0.996
6:37360554:T:A	W74R	0.995
6:37360554:T:C	W74R	0.995
6:37368484:A:C	S81R	0.995
6:37368486:T:A	S81R	0.995
6:37368486:T:G	S81R	0.995
6:37377006:T:G	C403W	0.995
6:37381174:A:C	S421R	0.995
6:37381176:T:A	S421R	0.995
6:37381176:T:G	S421R	0.995
6:37381181:G:A	C423Y	0.995
6:37381222:T:A	C437S	0.995
6:37381223:G:C	C437S	0.995
6:37381231:T:C	C440R	0.995
6:37377013:T:A	C406S	0.994

dbSNP variants (sampled 300 via entrez): RS1000055161 (6:37353885 G>A,C), RS1000143274 (6:37393864 C>T), RS1000223171 (6:37387465 C>T), RS1000327768 (6:37377944 A>C), RS1000456758 (6:37357282 A>C), RS1000465065 (6:37377641 G>C), RS1000515082 (6:37394285 A>T), RS1000557304 (6:37388917 A>C), RS1000571078 (6:37382904 C>T), RS1000632665 (6:37384376 A>C), RS1000735570 (6:37380534 A>G), RS1000865891 (6:37375711 C>A,T), RS1000895239 (6:37375264 C>T), RS1000932221 (6:37367864 A>G), RS1001025153 (6:37382689 G>A)

Disease associations

OMIM: gene MIM:611685 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002481_11	Acne (severe)	2.000000e-06
GCST005042_8	Restless legs syndrome	3.000000e-26

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2284922	Efficacy	3	carboplatin;docetaxel;trastuzumab	Breast Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2284922	RNF8	3	2.50	1	carboplatin;docetaxel;trastuzumab

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
pradimicin-IRD	affects response to substance, affects expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment	1
salinomycin	decreases expression	1
manganese chloride	increases abundance, increases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
Temozolomide	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Cadmium	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases response to substance, increases expression	1
Doxorubicin	affects expression, affects response to substance	1
Ketoconazole	decreases expression	1
Manganese	increases abundance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TJ45	HAP1 RNF8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.