RNF168

Summary

RNF168 (ring finger protein 168, HGNC:26661) is a protein-coding gene on chromosome 3q29, encoding E3 ubiquitin-protein ligase RNF168 (Q8IYW5). E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. It is a selective cancer dependency (DepMap: 50.1% of cell lines).

This gene encodes an E3 ubiquitin ligase protein that contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-DNA and protein-protein interactions. The protein is involved in DNA double-strand break (DSB) repair. Mutations in this gene result in Riddle syndrome.

Source: NCBI Gene 165918 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RIDDLE syndrome (Definitive, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 406 total — 28 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 50.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_152617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26661
Approved symbol	RNF168
Name	ring finger protein 168
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	FLJ35794
Ensembl gene	ENSG00000163961
Ensembl biotype	protein_coding
OMIM	612688
Entrez	165918

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000318037, ENST00000437070

RefSeq mRNA: 1 — MANE Select: NM_152617 NM_152617

CCDS: CCDS3317

Canonical transcript exons

ENST00000318037 — 6 exons

Exon	Start	End
ENSE00001127480	196488607	196488683
ENSE00001257846	196468783	196472772
ENSE00001257854	196502873	196503768
ENSE00003485610	196487399	196487578
ENSE00003686563	196483770	196483891
ENSE00003690104	196475231	196475312

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 96.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.9403 / max 334.5969, expressed in 1807 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46362	11.8933	1766
46361	7.6704	1679
46360	1.0645	630
46359	0.4289	239
46363	0.3561	154
46358	0.2847	122
46353	0.1635	50
46356	0.0789	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	96.32	gold quality
tendon of biceps brachii	UBERON:0008188	93.92	gold quality
epithelial cell of pancreas	CL:0000083	93.69	gold quality
parietal pleura	UBERON:0002400	92.91	gold quality
visceral pleura	UBERON:0002401	92.43	gold quality
calcaneal tendon	UBERON:0003701	92.13	gold quality
tendon	UBERON:0000043	92.03	gold quality
epithelium of nasopharynx	UBERON:0001951	91.72	gold quality
germinal epithelium of ovary	UBERON:0001304	91.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.58	gold quality
upper arm skin	UBERON:0004263	90.40	gold quality
vastus lateralis	UBERON:0001379	89.91	gold quality
ileal mucosa	UBERON:0000331	89.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.34	gold quality
biceps brachii	UBERON:0001507	89.34	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.19	gold quality
left ventricle myocardium	UBERON:0006566	89.19	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.91	gold quality
quadriceps femoris	UBERON:0001377	88.73	gold quality
palpebral conjunctiva	UBERON:0001812	88.60	gold quality
tibia	UBERON:0000979	88.59	gold quality
trabecular bone tissue	UBERON:0002483	88.51	gold quality
layer of synovial tissue	UBERON:0007616	88.32	gold quality
esophagus squamous epithelium	UBERON:0006920	88.21	gold quality
gingival epithelium	UBERON:0001949	88.08	gold quality
deltoid	UBERON:0001476	87.99	gold quality
testis	UBERON:0000473	87.95	gold quality
skin of hip	UBERON:0001554	87.89	gold quality
left testis	UBERON:0004533	87.72	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.37
E-ENAD-17	no	316.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

140 targeting RNF168, 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-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 50.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance. (PMID:19203579)
• RNF168 is a ubiquitin ligase that functions as chromatin modifier, through histone ubiquitination; upon DNA lesions, RNF168 is recruited to DNA damage response foci where it contributes to increase the amount of ubiquitinated proteins. (PMID:19500350)
• 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 RNF168 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)
• identification of a novel ubiquitin binding domain present in RNF168, and characterized the interaction surface with ubiquitin, centered on two Leu residues (PMID:21041483)
• 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)
• 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)
• this study reveals that human NIPBL is a novel protein recruited to DSB sites, and the recruitment is controlled by MDC1, RNF168 and HP1gamma. (PMID:21784059)
• Data show that depletion of RNF8, as well as of the E3 ligase RNF168, reduces telomere-induced genome instability. (PMID:21857671)
• 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)
• Inactivation of K13 and K15 reduces RNF168- dependent ubiquitination of histones H2As, while inactivation of both N- and C-terminal sites completely abolishes histone ubiquitination. (PMID:22713238)
• RNF168, its paralog RNF169, RAD18, and the BRCA1-interacting RAP80 protein accumulate at DNA double strand break sites through the use of bipartite modules composed of ubiquitin binding domains. (PMID:22742833)
• Ubiquitin-dependent signaling during the DNA damage response (DDR) to double-strand breaks is initiated by two E3 ligases, RNF8 and RNF168, targeting histone H2A and H2AX. Study shows that ubiquitin chains per se are insufficient for signaling, but RNF168 target ubiquitination is required for DDR. (PMID:22980979)
• RNF168 is important for defects in homologous recombination caused by loss of the BRCA1 in breast cancer cells. (PMID:23055523)
• Unlike RNF8, RNF168 RING domain did not stably associate with UBC13 at double-stranded DNA breaks in vitro or in vivo. (PMID:23255131)
• study unveils a functional link between DNA damage-induced poly(ADP-ribosyl)ation, SMARCA5-mediated chromatin remodeling and RNF168-dependent signaling and repair of DSBs. (PMID:23264744)
• RNF168, in complex with RAD6A or RAD6B, is activated in the DNA-damage-induced protein ubiquitination cascade. (PMID:23525009)
• findings implicate USP44 in negative regulation of the RNF8/RNF168 pathway (PMID:23615962)
• Taken together, the results suggested that USP3 is a negative regulator of ubiquitination signaling, counteracting RNF168- and RNF8-mediated ubiquitination (PMID:24196443)
• RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. (PMID:24217620)
• Before their localization to DNA double strand breaks, RNF168 interacts with 53BP1 and modifies it through the addition of a chain of ubiquitin-polypeptides. (PMID:24324146)
• The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro (PMID:24603765)
• The E3 ligase RNF168 promotes both H2A ubiquitylation and neddylation. RNF168 is itself a substrate for NEDD8, and neddylation of RNF168 is necessary for its E3 ubiquitin activity. (PMID:24634510)
• 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)
• The ubiquitin ligase RNF168 is strictly dependent on the activity that UbK27 is required to promote chromatin ubiquitination following DNA damage. (PMID:25578731)
• Results reveal an important role of USP7 in regulating ubiquitin-dependent signaling via stabilization of RNF168. (PMID:25894431)
• CK2/WIP1-mediated modulation of LSD1 phosphorylation facilitates RNF168-dependent ubiquitination and recruitment of 53BP1 to the DNA damage sites. (PMID:25999347)
• The association of RNF168 with PML NBs resulted in increased ubiquitylation. (PMID:26675234)
• RNF168 interacts with TOP2alpha to mediate its polyubiquitylation and RNF168 deficiency confers resistance to ICRF-193, a TOP2 catalytic inhibitor, and cytotoxic anti-cancer drug etoposide in cultured human cancers cells. (PMID:27558965)
• deregulated RNF168/53BP1 pathway could promote tumorigenesis by selecting for a more robust, better stress-adapted cancer cell phenotype, through altered DNA repair, fueling genomic instability and tumor heterogeneity (PMID:27841863)
• Further mining of the UBE2U interactome uncovered its cognate E3 RNF17 as a novel factor that, via the radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome protein RNF168, enforces DNA damage responses. (PMID:27903633)
• The findings demonstrate that RNF168 couples PALB2-dependent homologous recombination to H2A ubiquitylation to promote DNA repair and preserve genome integrity. (PMID:28240985)
• We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had Diamond-Blackfan anemia (DBA).we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. (PMID:28432740)
• Ubiquitin ligases RNF168, RNF169, and RAD18 specifically bind histone H2A Lys13/15-ubiquitylated nucleosomes. 53BP1 chromatin recruitment may be activated by RNF168 and blocked by RNF169 and RAD18. (PMID:28506460)
• data are in line with a model in which HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DDR. (PMID:29127375)
• Ub-interacting residues in UDM2 prevent the accumulation of RNF168 to double-strand breaks sites in U2OS cells, whereas those in UDM1 have little effect. (PMID:29330428)
• The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168 in tumor cell lines. (PMID:29403037)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf168	ENSDARG00000112483
mus_musculus	Rnf168	ENSMUSG00000014074
rattus_norvegicus	Rnf168	ENSRNOG00000043345
caenorhabditis_elegans		WBGENE00011366

Paralogs (1): RNF169 (ENSG00000166439)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF168 — Q8IYW5 (reviewed: Q8IYW5)

Alternative names: RING finger protein 168, RING-type E3 ubiquitin transferase RNF168

All UniProt accessions (2): Q8IYW5, F8WD60

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of ‘Lys-63’-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of ‘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. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate ‘Lys-63’-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of ‘Lys-13’ and ‘Lys-15’ of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).

Subunit / interactions. Monomer. Interacts with UBE2N/UBC13.

Subcellular location. Nucleus.

Post-translational modifications. Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs). Ubiquitinated.

Disease relevance. Riddle syndrome (RIDL) [MIM:611943] An autosomal recessive disorder characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MIU motif (motif interacting with ubiquitin) mediates the interaction with both ‘Lys-48’- and ‘Lys-63’-linked ubiquitin chains. The UMI motif mediates interaction with ubiquitin with a preference for ‘Lys-63’-linked ubiquitin. The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs).

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RNF168 family.

RefSeq proteins (1): NP_689830* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR034725	RNF168	Family
IPR051657	RNF168/RNF169_E3_ubiq-ligase	Family

Pfam: PF14447

UniProt features (54 total): helix 9, modified residue 8, mutagenesis site 8, compositionally biased region 6, short sequence motif 5, region of interest 4, turn 4, sequence variant 3, cross-link 2, strand 2, chain 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5XIS	X-RAY DIFFRACTION	1.78
5XIU	X-RAY DIFFRACTION	1.8
8UQA	X-RAY DIFFRACTION	2.05
3L11	X-RAY DIFFRACTION	2.12
5XIT	X-RAY DIFFRACTION	2.25
8UQ9	X-RAY DIFFRACTION	2.3
8UQ8	X-RAY DIFFRACTION	2.34
8UQB	X-RAY DIFFRACTION	2.48
5YDK	X-RAY DIFFRACTION	2.5
4GB0	X-RAY DIFFRACTION	2.6
8UQC	X-RAY DIFFRACTION	2.61
8SMX	ELECTRON MICROSCOPY	3.2
8SMY	ELECTRON MICROSCOPY	3.2
8SMZ	ELECTRON MICROSCOPY	3.2
8SN0	ELECTRON MICROSCOPY	3.2
8UPF	ELECTRON MICROSCOPY	3.2
8X7I	ELECTRON MICROSCOPY	3.27
8X7K	ELECTRON MICROSCOPY	3.27
8SMW	ELECTRON MICROSCOPY	3.3
8SN1	ELECTRON MICROSCOPY	3.3
8X7J	ELECTRON MICROSCOPY	3.39
8UQE	X-RAY DIFFRACTION	3.56
8SN2	ELECTRON MICROSCOPY	3.6
8TXW	ELECTRON MICROSCOPY	3.6
8SN4	ELECTRON MICROSCOPY	3.7
8SN6	ELECTRON MICROSCOPY	3.7
8SN7	ELECTRON MICROSCOPY	3.7
8SN8	ELECTRON MICROSCOPY	3.7
8TXX	ELECTRON MICROSCOPY	3.7
8SN3	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYW5-F1	61.97	0.30

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 (10): 70, 134, 197, 362, 411, 414, 415, 470, 210, 528

Mutagenesis-validated functional residues (8):

Position	Phenotype
16	does not affect ability to bind ubiquitin and localization to dsbs sites, while it abolishes e3 ligase activity; when as
18	abolishes ability to ubiquitinate kdm4a.
19	does not affect ability to bind ubiquitin and localization to dsbs sites, while it abolishes e3 ligase activity; when as
57	does not affect the monomeric structure but abolishes ability to monoubiquitinate h2a in nucleosomes.
149–150	impaired ability to bind ubiquitin.
179	impairs ability to form foci following ionizing radiation and impaired binding to ’lys-63’-linked ubiquitin.
450	still able to bind ’lys-63’-linked ubiquitin.
476–477	does not affect ubiquitin-binding but impairs recruitment to dsbs.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
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-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
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-597592	Post-translational protein modification
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73894	DNA Repair

MSigDB gene sets: 312 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_B_CELL_ACTIVATION, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_IMMUNOGLOBULIN_PRODUCTION, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (19): 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), protein ubiquitination (GO:0016567), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), interstrand cross-link repair (GO:0036297), epigenetic regulation of gene expression (GO:0040029), isotype switching (GO:0045190), positive regulation of DNA repair (GO:0045739), protein K63-linked ubiquitination (GO:0070534), double-strand break repair via classical nonhomologous end joining (GO:0097680), DNA repair-dependent chromatin remodeling (GO:0140861), DNA damage checkpoint signaling (GO:0000077), DNA metabolic process (GO:0006259), DNA repair (GO:0006281), chromatin organization (GO:0006325), response to radiation (GO:0009314)

GO Molecular Function (13): chromatin binding (GO:0003682), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), nucleosome binding (GO:0031491), histone binding (GO:0042393), ubiquitin binding (GO:0043130), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), histone ubiquitin ligase activity (GO:0140852), histone H2AK15 ubiquitin ligase activity (GO:0140858), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872), ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (7): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), protein-containing complex (GO:0032991), site of double-strand break (GO:0035861), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
DNA Double-Strand Break Repair	3
SUMO E3 ligases SUMOylate target proteins	1
DNA Double Strand Break Response	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1
Post-translational protein modification	1
SUMOylation	1
DNA Repair	1
Homology Directed Repair	1
Metabolism of proteins	1
Cell Cycle Checkpoints	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA repair	3
chromatin remodeling	2
DNA damage response	2
binding	2
cellular anatomical structure	2
double-strand break repair	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cellular response to stress	1
response to radiation	1
protein modification by small protein conjugation	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
regulation of gene expression	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
protein polyubiquitination	1
double-strand break repair via nonhomologous end joining	1
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
nucleic acid metabolic process	1
DNA metabolic process	1
cellular component organization	1
response to abiotic stimulus	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
chromatin binding	1
protein-containing complex binding	1
protein binding	1
ubiquitin-like protein binding	1
polyubiquitin modification-dependent protein binding	1
ubiquitin protein ligase activity	1
histone modifying activity	1
histone H2A ubiquitin ligase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF168	RNF8	O76064	996
RNF168	MDC1	Q14676	995
RNF168	UBE2N	P61088	990
RNF168	VPS29	Q9UBQ0	985
RNF168	TP53BP1	Q12888	973
RNF168	H1-0	P07305	950
RNF168	H2AC19	P20670	925
RNF168	H2AC20	Q16777	925
RNF168	BRCA1	P38398	921
RNF168	PALB2	Q86YC2	890
RNF168	UIMC1	Q96RL1	887
RNF168	OTUB1	Q96FW1	875
RNF168	RAD18	Q9NS91	845
RNF168	ATM	Q13315	821
RNF168	H2AX	P16104	815

IntAct

50 interactions, top by confidence:

A	B	Type	Score
	RNF168	psi-mi:“MI:0915”(physical association)	0.680
RNF168		psi-mi:“MI:0407”(direct interaction)	0.680
RNF11	RNF168	psi-mi:“MI:0915”(physical association)	0.670
RNF168	RNF11	psi-mi:“MI:0915”(physical association)	0.670
ALAS1	RNF168	psi-mi:“MI:0915”(physical association)	0.560
RNF168	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
DCTN1	RNF168	psi-mi:“MI:0915”(physical association)	0.560
WFS1	RNF168	psi-mi:“MI:0915”(physical association)	0.560
SNCA	RNF168	psi-mi:“MI:0915”(physical association)	0.560
TP53BP1	RNF168	psi-mi:“MI:0403”(colocalization)	0.450
RNF168	H2AC25	psi-mi:“MI:0407”(direct interaction)	0.440
RNF168	H1-0	psi-mi:“MI:0407”(direct interaction)	0.440
RNF168	UBB	psi-mi:“MI:0407”(direct interaction)	0.440
JMJD1C	RNF168	psi-mi:“MI:0915”(physical association)	0.400
RNF168	H1-10	psi-mi:“MI:0915”(physical association)	0.400
RNF168	H1-2	psi-mi:“MI:0915”(physical association)	0.400
RNF168	PDIA4	psi-mi:“MI:0915”(physical association)	0.400
UBE2N	RNF168	psi-mi:“MI:0915”(physical association)	0.400
RNF168	UBE2N	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (209): RNF168 (Biochemical Activity), RNF168 (Affinity Capture-Western), UBC (Reconstituted Complex), KDM1A (Reconstituted Complex), RNF168 (Reconstituted Complex), RNF168 (Affinity Capture-Western), RNF168 (Affinity Capture-Western), PSMD11 (Affinity Capture-MS), TBP (Affinity Capture-MS), SRCAP (Affinity Capture-MS), CCDC174 (Affinity Capture-MS), NUB1 (Affinity Capture-MS), RPRD1B (Affinity Capture-MS), RNF168 (Affinity Capture-MS), FAM45A (Affinity Capture-MS)

ESM2 similar proteins: A0P8Z5, B0KYV5, B1WC58, B2RYR0, F1LR10, F6SNN2, O75128, O75410, P51826, P61590, P61591, P61592, P61593, P61594, Q3USH1, Q501R9, Q5IFK1, Q5PQK4, Q5R8C5, Q5SU73, Q5SWA1, Q5U5Q9, Q6NZF1, Q6P1D7, Q6P7W0, Q6PJW8, Q6Y685, Q6ZSG2, Q6ZVT6, Q7TT79, Q80XI1, Q80XJ2, Q80YR6, Q86T90, Q8BFU3, Q8C9B9, Q8IY92, Q8IYW5, Q8ND24, Q8NEM0

Diamond homologs: B0BLU1, B2RYR0, E7FAP1, P19474, Q0IIM1, Q1L721, Q1XHT8, Q6INS5, Q6P9F5, Q7T308, Q80XJ2, Q8IYW5, D3YY23, E1BD59, Q17RB8, Q1L5Z9, Q2YEM9, Q496Y0, Q5C8T8, Q810I2, Q8HXH0, Q8NCN4, A0JN74, A0JPQ4, A6NLI5, A7E320, B1H278, O19085, O54952, O60106, O64425, P10862, P15918, P33288, P38398, P48754, Q02084, Q02398, Q03605, Q14258

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
H2AC11	up-regulates	RNF168	binding
RNF168	unknown	H2AX	ubiquitination
“Histone H2B”	up-regulates	RNF168	binding
UBR5	“down-regulates quantity”	RNF168	ubiquitination
TRIP12	“down-regulates activity”	RNF168	ubiquitination
RNF168	“up-regulates quantity”	“Histone H2A”	ubiquitination
L3MBTL2	“down-regulates quantity”	RNF168	binding
RNF168	up-regulates	DNA_repair
Ub:E2	“up-regulates activity”	RNF168	ubiquitination
RNF168	“up-regulates activity”	BLM	ubiquitination
RNF168	down-regulates	H1-2	polyubiquitination
DGCR8	“up-regulates activity”	RNF168	binding
RNF168	“up-regulates quantity”	TP53BP1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	33.3×	1e-04
Processing of DNA double-strand break ends	5	25.9×	1e-04
Antigen processing: Ubiquitination & Proteasome degradation	5	8.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via homologous recombination	5	24.4×	3e-04
DNA damage response	5	8.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	8
Uncertain significance	184
Likely benign	143
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1362017	NM_152617.4(RNF168):c.150_151del (p.Cys50fs)	Pathogenic
1377590	NM_152617.4(RNF168):c.640_644del (p.Lys213_Lys214insTer)	Pathogenic
1394900	NM_152617.4(RNF168):c.644del (p.Ser215fs)	Pathogenic
1429795	NM_152617.4(RNF168):c.975dup (p.Cys326fs)	Pathogenic
1436392	NM_152617.4(RNF168):c.194_198del (p.His65fs)	Pathogenic
1502151	NM_152617.4(RNF168):c.1130dup (p.Cys378fs)	Pathogenic
1907142	NM_152617.4(RNF168):c.994C>T (p.Arg332Ter)	Pathogenic
2010096	NM_152617.4(RNF168):c.510del (p.Glu170fs)	Pathogenic
2146079	NM_152617.4(RNF168):c.655_658del (p.Gln219fs)	Pathogenic
2148010	NM_152617.4(RNF168):c.477_480del (p.Ala161fs)	Pathogenic
2427398	NC_000003.11:g.(?196215458)(196215574_?)del	Pathogenic
2427399	NC_000003.11:g.(?196210621)(196215574_?)del	Pathogenic
2720076	NM_152617.4(RNF168):c.350_351del (p.Arg117fs)	Pathogenic
2726263	NM_152617.4(RNF168):c.560del (p.Asn187fs)	Pathogenic
2770341	NM_152617.4(RNF168):c.94_95insC (p.Asn32fs)	Pathogenic
2776100	NM_152617.4(RNF168):c.733C>T (p.Gln245Ter)	Pathogenic
3247061	NC_000003.11:g.(?196202082)(196202203_?)del	Pathogenic
3247062	NC_000003.11:g.(?196198690)(196202203_?)del	Pathogenic
3610342	NM_152617.4(RNF168):c.658dup (p.Arg220fs)	Pathogenic
3657553	NM_152617.4(RNF168):c.1214_1230del (p.Ala405fs)	Pathogenic
3682751	NM_152617.4(RNF168):c.662dup (p.Asn221fs)	Pathogenic
3683421	NM_152617.4(RNF168):c.377del (p.Lys126fs)	Pathogenic
3722128	NM_152617.4(RNF168):c.975_976del (p.Val327fs)	Pathogenic
3724991	NM_152617.4(RNF168):c.1290_1293del (p.Asp431fs)	Pathogenic
4707102	NM_152617.4(RNF168):c.891del (p.Met298fs)	Pathogenic
4777058	NM_152617.4(RNF168):c.212_213del (p.Leu71fs)	Pathogenic
487	NM_152617.4(RNF168):c.397dup (p.Ala133fs)	Pathogenic
688034	GRCh37/hg19 3q29(chr3:196204149-196232328)x1	Pathogenic
1985421	NM_152617.4(RNF168):c.559-1_560del	Likely pathogenic
2847827	NM_152617.4(RNF168):c.558+1G>T	Likely pathogenic

SpliceAI

1202 predictions. Top by Δscore:

Variant	Effect	Δscore
3:196472769:TGTC:T	acceptor_gain	1.0000
3:196472771:TC:T	acceptor_gain	1.0000
3:196472771:TCC:T	acceptor_loss	1.0000
3:196472772:CC:C	acceptor_gain	1.0000
3:196472773:C:CC	acceptor_gain	1.0000
3:196475226:CATA:C	donor_loss	1.0000
3:196475227:ATAC:A	donor_loss	1.0000
3:196475228:TA:T	donor_loss	1.0000
3:196475229:A:C	donor_loss	1.0000
3:196475230:C:CA	donor_loss	1.0000
3:196475310:TAC:T	acceptor_gain	1.0000
3:196475312:CCTAA:C	acceptor_loss	1.0000
3:196475313:C:CC	acceptor_gain	1.0000
3:196475313:CTAAA:C	acceptor_loss	1.0000
3:196483896:A:T	acceptor_gain	1.0000
3:196483898:CAA:C	acceptor_gain	1.0000
3:196483899:A:T	acceptor_gain	1.0000
3:196483900:A:AC	acceptor_gain	1.0000
3:196483900:A:C	acceptor_gain	1.0000
3:196487397:A:AC	donor_gain	1.0000
3:196487398:C:CC	donor_gain	1.0000
3:196487413:G:C	donor_gain	1.0000
3:196487421:G:A	donor_gain	1.0000
3:196487427:T:TA	donor_gain	1.0000
3:196487576:CACCT:C	acceptor_gain	1.0000
3:196487580:T:C	acceptor_gain	1.0000
3:196488602:CCTA:C	donor_loss	1.0000
3:196488603:CTA:C	donor_loss	1.0000
3:196488605:A:AC	donor_gain	1.0000
3:196488605:AC:A	donor_gain	1.0000

AlphaMissense

3768 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:196502991:C:A	W61C	0.996
3:196502991:C:G	W61C	0.996
3:196502993:A:G	W61R	0.996
3:196502993:A:T	W61R	0.996
3:196503023:A:G	C51R	0.995
3:196503055:A:G	F40S	0.995
3:196503068:A:G	C36R	0.994
3:196503094:A:T	V27D	0.993
3:196503128:A:G	C16R	0.993
3:196503011:G:T	R55S	0.992
3:196503014:A:G	C54R	0.991
3:196503097:G:T	P26H	0.991
3:196503059:A:G	C39R	0.990
3:196503127:C:G	C16S	0.990
3:196503128:A:T	C16S	0.990
3:196503043:A:T	V44D	0.989
3:196503054:G:C	F40L	0.989
3:196503054:G:T	F40L	0.989
3:196503056:A:G	F40L	0.989
3:196503066:A:C	C36W	0.989
3:196503083:A:G	C31R	0.989
3:196503012:A:C	C54W	0.988
3:196503021:A:C	C51W	0.988
3:196503055:A:C	F40C	0.988
3:196488626:T:G	Y120S	0.987
3:196503013:C:T	C54Y	0.987
3:196503067:C:T	C36Y	0.987
3:196503067:C:G	C36S	0.986
3:196503068:A:T	C36S	0.986
3:196503075:G:C	H33Q	0.986

dbSNP variants (sampled 300 via entrez): RS1000049665 (3:196473597 G>A), RS1000213161 (3:196494014 G>A), RS1000263710 (3:196486834 C>T), RS1000281318 (3:196478697 C>T), RS1000286622 (3:196487003 C>T), RS1000488677 (3:196492129 C>T), RS1000517209 (3:196488080 A>C), RS1000547409 (3:196492889 C>G,T), RS1000587229 (3:196489138 G>A), RS1000834755 (3:196502560 C>T), RS1000936149 (3:196495818 A>G), RS1000948858 (3:196502358 G>A), RS1000979412 (3:196470673 C>G,T), RS1001017447 (3:196501117 C>G,T), RS1001111926 (3:196497684 A>G)

Disease associations

OMIM: gene MIM:612688 | disease phenotypes: MIM:611943

GenCC curated gene-disease

Disease	Classification	Inheritance
RIDDLE syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
RIDDLE syndrome	Definitive	AR

Mondo (1): RIDDLE syndrome (MONDO:0012764)

Orphanet (1): RIDDLE syndrome (Orphanet:420741)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000388	Otitis media
HP:0000524	Conjunctival telangiectasia
HP:0000712	Emotional lability
HP:0000958	Dry skin
HP:0001009	Telangiectasia
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001328	Specific learning disability
HP:0001369	Arthritis
HP:0001824	Weight loss
HP:0001954	Recurrent fever
HP:0001999	Abnormal facial shape
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002090	Pneumonia
HP:0002091	Restrictive ventilatory defect
HP:0002206	Pulmonary fibrosis
HP:0002312	Clumsiness
HP:0002315	Headache
HP:0002500	Abnormal cerebral white matter morphology
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002850	Decreased circulating total IgM
HP:0002878	Respiratory failure
HP:0004315	Decreased circulating IgG concentration
HP:0004322	Short stature
HP:0004429	Recurrent viral infections

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001343_7	Fat distribution (HIV)	4.000000e-06
GCST010244_200	Triglyceride levels	1.000000e-08
GCST90002390_201	Mean corpuscular hemoglobin	6.000000e-15
GCST90002392_730	Mean corpuscular volume	3.000000e-23
GCST90002396_263	Mean reticulocyte volume	3.000000e-16
GCST90002397_97	Mean spheric corpuscular volume	4.000000e-20

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004530	triglyceride measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567453	Riddle Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169175 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.17	Kd	6820	nM	CHEMBL5201307

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[6-[[2-amino-6-[1-(3,4,5-trimethoxyphenyl)triazol-4-yl]quinazolin-4-yl]amino]hexyl]pentanamide	1848872: Binding affinity to RNF168 (unknown origin) by MST assay	kd	6.8200	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression, affects expression, affects response to substance	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cycloheximide	decreases expression, increases reaction	1
Endosulfan	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5099881	Binding	Binding affinity to RNF168 in human HCT-116 cells lysates at 10 uM by pull-down based immunoblot assay	A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62. — J Med Chem

Clinical trials (associated diseases)

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