RIF1

Summary

RIF1 (replication timing regulatory factor 1, HGNC:23207) is a protein-coding gene on chromosome 2q23.3, encoding Telomere-associated protein RIF1 (Q5UIP0). Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs. It is a selective cancer dependency (DepMap: 16.1% of cell lines).

This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 55183 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 655 total — 14 pathogenic, 11 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 16.1% of screened cell lines
• MANE Select transcript: NM_018151

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23207
Approved symbol	RIF1
Name	replication timing regulatory factor 1
Location	2q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12870, FLJ10599
Ensembl gene	ENSG00000080345
Ensembl biotype	protein_coding
OMIM	608952
Entrez	55183

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000243326, ENST00000414861, ENST00000428287, ENST00000430328, ENST00000444746, ENST00000453091, ENST00000454583, ENST00000457745, ENST00000467762, ENST00000484077, ENST00000494333, ENST00000498041, ENST00000925469, ENST00000925470, ENST00000925471, ENST00000925472, ENST00000925473, ENST00000925474

RefSeq mRNA: 4 — MANE Select: NM_018151 NM_001177663, NM_001177664, NM_001177665, NM_018151

CCDS: CCDS2194, CCDS54406

Canonical transcript exons

ENST00000444746 — 36 exons

Exon	Start	End
ENSE00000840485	151428784	151428922
ENSE00000840486	151433077	151433228
ENSE00000840487	151435463	151435580
ENSE00001513325	151474857	151482172
ENSE00001595111	151445338	151445445
ENSE00001623766	151462242	151462322
ENSE00001646420	151468474	151468551
ENSE00001656464	151457761	151457963
ENSE00001674552	151473964	151474072
ENSE00001685288	151443529	151443709
ENSE00001686793	151468641	151468756
ENSE00001700514	151454895	151455159
ENSE00001702784	151458811	151458910
ENSE00001719943	151469711	151469864
ENSE00001721448	151451606	151451705
ENSE00001735962	151461138	151461289
ENSE00001741010	151462412	151462466
ENSE00001752460	151460000	151460119
ENSE00001752560	151456578	151456620
ENSE00001754052	151443259	151443329
ENSE00001757638	151462884	151466120
ENSE00001760575	151446426	151446575
ENSE00001761753	151468000	151468146
ENSE00003496940	151438684	151438746
ENSE00003567684	151411260	151411338
ENSE00003572463	151416561	151416688
ENSE00003582386	151441905	151441991
ENSE00003589471	151410414	151410527
ENSE00003642874	151440027	151440127
ENSE00003643500	151422950	151423042
ENSE00003644514	151420190	151420379
ENSE00003648672	151436827	151437003
ENSE00003660515	151416807	151416901
ENSE00003664026	151414823	151414919
ENSE00003671531	151437241	151437351
ENSE00003893132	151409902	151410033

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 96.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8151 / max 271.3708, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23052	23.4358	1815
23053	1.0426	664
23057	0.3368	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.91	gold quality
gastrocnemius	UBERON:0001388	96.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.51	gold quality
muscle of leg	UBERON:0001383	96.40	gold quality
calcaneal tendon	UBERON:0003701	95.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.10	gold quality
tendon	UBERON:0000043	94.43	gold quality
secondary oocyte	CL:0000655	93.88	gold quality
oocyte	CL:0000023	93.66	gold quality
adrenal tissue	UBERON:0018303	93.21	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.82	gold quality
corpus callosum	UBERON:0002336	92.00	gold quality
medial globus pallidus	UBERON:0002477	91.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.59	gold quality
globus pallidus	UBERON:0001875	91.53	gold quality
skeletal muscle organ	UBERON:0014892	90.70	gold quality
muscle organ	UBERON:0001630	90.67	gold quality
lateral globus pallidus	UBERON:0002476	90.40	gold quality
endothelial cell	CL:0000115	90.11	gold quality
sural nerve	UBERON:0015488	89.40	gold quality
inferior vagus X ganglion	UBERON:0005363	89.38	gold quality
pericardium	UBERON:0002407	89.36	gold quality
tendon of biceps brachii	UBERON:0008188	89.07	gold quality
pylorus	UBERON:0001166	88.63	gold quality
ventricular zone	UBERON:0003053	88.53	gold quality
sperm	CL:0000019	88.52	gold quality
nipple	UBERON:0002030	88.19	gold quality
trigeminal ganglion	UBERON:0001675	88.18	gold quality
tonsil	UBERON:0002372	88.07	gold quality
colonic epithelium	UBERON:0000397	87.99	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	46.31
E-ANND-3	yes	8.08
E-MTAB-6911	no	277.94
E-GEOD-99795	no	160.88

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ZSCAN4	Repression

miRNA regulators (miRDB)

148 targeting RIF1, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1250-3P	99.96	70.04	4038

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 34)

• Rif1 functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred. (PMID:15342490)
• In telophase, hRif1 localized to chromosomes, and in interphase, it was intranuclear. These results define a novel subcellular localization behavior for hRif1 during the cell cycle. (PMID:15583028)
• High RIF1 expression is associated with breast tumors. (PMID:19483192)
• Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher-order chromatin architecture (PMID:22850674)
• RIF1 as the critical effector of 53BP1 during DSB repair (PMID:23333306)
• RIF1 not only acts downstream of 53BP1 and counteracts BRCA1-mediated end resection but also has a secondary role in promoting BLM function in DNA repair. (PMID:23486525)
• RIF1 is an important component in DNA damage response signaling. [Review] (PMID:24462468)
• These data reveal a thus far unrecognized function for Rif1 in the resolution of ultrafine DNA bridges during anaphase to protect genomic integrity. (PMID:26256213)
• 53BP1/RIF1 has a role in limiting BRCA1/CtIP-mediated end resection to control double strand break repair pathway choice (PMID:27494840)
• In pancreatic cancer cells, RIF1 gene expression in the stem cell-positive cell line was 256 times that seen in the stem cell-negative cell line. RIF1 may be one of the genes that plays an important role in the diagnoses and therapeutic treatment of pancreatic cancer (PMID:27917791)
• Rif1 can mediate MCM dephosphorylation at replication forks and that the stability of dephosphorylated replisomes strongly depends on Chk1 activity. (PMID:28273463)
• DDX1, a RNA helicase also implicated in DSB repair, interacts with RIF1. Recruitment of DDX1 to DSBs is dependent on RIF1. DDX1 and RIF1 have different nucleic acid requirements for accumulation at DSBs, with RNA-DNA hybrids required for DDX1 accrual at DSBs, and single-strand RNA required for accumulation of RIF1 at these sites. (PMID:28544931)
• Data suggest that SCAI inhibits RIF1 function to allow BRCA1-mediated repair, which possibly includes alt-NHEJ and resection-dependent NHEJ in G1, as well as HDR in S/G2. (PMID:28700933)
• Low Rap1-interacting factor 1 expression is associated with Hodgkin lymphoma. (PMID:28786706)
• the differential H4K20 methylation status between pre-replicative and post-replicative DNA represents an intrinsic mechanism that locally ensures appropriate recruitment of the 53BP1-RIF1-MAD2L2 complex at DNA double strand breaks. (PMID:29160738)
• Study reported that RIF1 is SUMOlyated in response to DNA damage and identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci. (PMID:29234018)
• Upregulation of RIF1 correlates with poor prognosis in Epithelial Ovarian Cancer. (PMID:29719287)
• data suggest that CST-Polalpha-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin (PMID:30022158)
• RIF1 expression is upregulated in EOC tissues and is closely correlated with FIGO stage and prognosis of EOC patients. Functionally, RIF1 knockdown suppressed the expression and promoter activity of hTERT and consequently inhibited the growth and CSC-like traits of EOC cells. (PMID:30075819)
• 53BP1 and RIF1 assemble a higher-order structure in the vicinity of damaged chromatin to protect it from unscheduled DNA-end resection. (PMID:31792447)
• we identified RIF1 as the critical effector of 53BP1. Inhibiting 53BP1 recruitment to damaged chromatin completely abolished the survival advantage after multifractionated irradiation and could not be reversed by suppressing excessive end resection. (PMID:31822909)
• The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress. (PMID:33141022)
• Variants in NEB and RIF1 genes on chr2q23 are associated with skeletal muscle index in Koreans: genome-wide association study. (PMID:33674626)
• Replication timing maintains the global epigenetic state in human cells. (PMID:33888635)
• Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action. (PMID:34260925)
• RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair. (PMID:34768871)
• CXCR4 and RIF1 overexpression induces resistance of epithelial ovarian cancer to cisplatin-based chemotherapy. (PMID:34916377)
• RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity. (PMID:35177609)
• Rif1-Dependent Control of Replication Timing. (PMID:35328102)
• Histone chaperone ASF1 acts with RIF1 to promote DNA end joining in BRCA1-deficient cells. (PMID:35472331)
• RIF1 suppresses the formation of single-stranded ultrafine anaphase bridges via protein phosphatase 1. (PMID:36719798)
• MiR-30a-5p Enhances Cisplatin Sensitivity by Downregulating RIF1 in Ovarian Cancer. (PMID:37437929)
• Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer. (PMID:37548940)
• Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer. (PMID:38244928)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rif1	ENSDARG00000062650
mus_musculus	Rif1	ENSMUSG00000036202
rattus_norvegicus	Rif1	ENSRNOG00000054901
drosophila_melanogaster	Rif1	FBGN0050085
caenorhabditis_elegans		WBGENE00008710
caenorhabditis_elegans		WBGENE00008958

Protein

Protein identifiers

Telomere-associated protein RIF1 — Q5UIP0 (reviewed: Q5UIP0)

Alternative names: Rap1-interacting factor 1 homolog

All UniProt accessions (3): Q5UIP0, H7BZN3, H7C2B5

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs. In response to DNA damage, interacts with ATM-phosphorylated TP53BP1. Interaction with TP53BP1 leads to dissociate the interaction between NUDT16L1/TIRR and TP53BP1, thereby unmasking the tandem Tudor-like domain of TP53BP1 and allowing recruitment to DNA DSBs. Once recruited to DSBs, RIF1 and TP53BP1 act by promoting NHEJ-mediated repair of DSBs. In the same time, RIF1 and TP53BP1 specifically counteract the function of BRCA1 by blocking DSBs resection via homologous recombination (HR) during G1 phase. Also required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs. Promotes NHEJ of dysfunctional telomeres.

Subunit / interactions. Interacts with TP53BP1 (when phosphorylated by ATM). May interact with TRF2. Interacts with SHLD2. Interacts with ERCC6 (via WHD region). Interacts with ASTE1.

Subcellular location. Nucleus. Chromosome. Telomere. Cytoplasm. Cytoskeleton. Spindle.

Tissue specificity. Highly expressed in testis.

Similarity. Belongs to the RIF1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5UIP0-1	1	yes
Q5UIP0-2	2

RefSeq proteins (4): NP_001171134, NP_001171135, NP_001171136, NP_060621* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR022031	Rif1_N	Domain

Pfam: PF12231

UniProt features (88 total): modified residue 47, compositionally biased region 12, region of interest 11, sequence variant 9, sequence conflict 7, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8RS8	X-RAY DIFFRACTION	1.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5UIP0-F1	54.07	0.19

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 (47): 402, 409, 782, 979, 1008, 1047, 1162, 1220, 1236, 1238, 1422, 1454, 1513, 1518, 1542, 1552, 1554, 1556, 1564, 1576 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)

MSigDB gene sets: 0 (showing top):

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), telomere maintenance (GO:0000723), DNA repair (GO:0006281), DNA damage response (GO:0006974), subtelomeric heterochromatin formation (GO:0031509), somatic stem cell population maintenance (GO:0035019), telomere maintenance in response to DNA damage (GO:0043247), negative regulation of gene expression, epigenetic (GO:0045814), positive regulation of isotype switching (GO:0045830), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of double-strand break repair via homologous recombination (GO:2000042), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (16): chromatin (GO:0000785), condensed chromosome (GO:0000793), female pronucleus (GO:0001939), male pronucleus (GO:0001940), nucleus (GO:0005634), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), site of double-strand break (GO:0035861), spindle midzone (GO:0051233), chromosome, telomeric repeat region (GO:0140445), chromosome, telomeric region (GO:0000781), chromosome (GO:0005694), cytoplasm (GO:0005737), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membraneless organelle	3
DNA metabolic process	2
DNA damage response	2
chromosome, telomeric region	2
chromosome	2
pronucleus	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
telomere organization	1
cellular response to stress	1
constitutive heterochromatin formation	1
stem cell population maintenance	1
telomere maintenance	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of isotype switching	1
positive regulation of DNA recombination	1
positive regulation of B cell activation	1
positive regulation of developmental process	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
double-strand break repair via nonhomologous end joining	1
positive regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
membrane	1
cell periphery	1
nucleus	1
nuclear envelope	1

Protein interactions and networks

STRING

1836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIF1	TP53BP1	Q12888	759
RIF1	PAXIP1	Q6ZW49	674
RIF1	MAD2L2	Q9UI95	653
RIF1	SHLD3	Q6ZNX1	519
RIF1	SHLD1	Q8IYI0	514
RIF1	TEN1	Q86WV5	509
RIF1	SHLD2	Q86V20	472
RIF1	HEATR1	Q9H583	426
RIF1	ASTE1	Q2TB18	424
RIF1	BLM	P54132	417
RIF1	MSL3	Q8N5Y2	415
RIF1	RNF168	Q8IYW5	393
RIF1	KDF1	Q8NAX2	391
RIF1	RBBP8	Q99708	356
RIF1	ATM	Q13315	343
RIF1	PALB2	Q86YC2	343

IntAct

254 interactions, top by confidence:

A	B	Type	Score
BLM	TOP3A	psi-mi:“MI:0914”(association)	0.890
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
RIF1	PPP1CA	psi-mi:“MI:0915”(physical association)	0.810
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
PPP1CA	CCDC85C	psi-mi:“MI:2364”(proximity)	0.670
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
AURKB	SEC16A	psi-mi:“MI:2364”(proximity)	0.570
RIF1	PPP1CC	psi-mi:“MI:0915”(physical association)	0.550
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC39A9	B4GALT5	psi-mi:“MI:0914”(association)	0.530
ASF1A	MCM4	psi-mi:“MI:0914”(association)	0.530

BioGRID (294): RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), MRGBP (Co-fractionation), NUDT21 (Co-fractionation), PPP2R1A (Co-fractionation), THOC6 (Co-fractionation), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), RIF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1I9LM04, A2WXU2, A4III8, B0M1H3, E1C2U2, F4HRS2, F4HSX9, F4I3Z5, F4I9T0, F4IIM1, F4IP13, F4KEY9, O23052, O24610, O48626, O80742, P40511, Q058P4, Q0WVF8, Q32PZ3, Q5N829, Q5PR66, Q5UIP0, Q5XK92, Q5ZMJ7, Q66GN3, Q6PR54, Q75EM1, Q7Z4Q2, Q84VX3, Q86XA9, Q8BGB2, Q8BQM4, Q8BWY9, Q8C3Y4, Q8GXP4, Q8GZN1, Q8L5R3, Q8L5Y0, Q8S8L9

Diamond homologs: E1C2U2, Q5UIP0, Q6PR54, Q9XZ34

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	RIF1	binding
RIF1	down-regulates	G1/S_transition
UHRF1	“down-regulates activity”	RIF1	polyubiquitination
TP53BP1	“up-regulates activity”	RIF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 219 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
TP53 Regulates Transcription of DNA Repair Genes	7	8.0×	6e-03
MAPK6/MAPK4 signaling	9	7.7×	1e-03
G2/M Checkpoints	8	6.8×	6e-03
G2/M DNA damage checkpoint	8	6.1×	7e-03
Regulation of TP53 Activity through Phosphorylation	8	6.0×	7e-03
Processing of DNA double-strand break ends	8	5.8×	7e-03
Transcriptional Regulation by TP53	13	5.1×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
DNA damage response	16	4.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	11
Uncertain significance	383
Likely benign	138
Benign	11

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1047890	GRCh37/hg19 2q21.3-23.3(chr2:136473383-152727396)	Pathogenic
1427957	NM_001164508.2(NEB):c.22966del (p.Val7656fs)	Pathogenic
1451650	NM_001164508.2(NEB):c.24376_24377insCC (p.Gln8126fs)	Pathogenic
1453846	NM_001164508.2(NEB):c.22175del (p.Lys7392fs)	Pathogenic
2023151	NM_001164508.2(NEB):c.24510dup (p.Lys8171fs)	Pathogenic
2030542	NM_001164508.2(NEB):c.22931del (p.Glu7644fs)	Pathogenic
2042915	NM_001164508.2(NEB):c.24469C>T (p.Gln8157Ter)	Pathogenic
212737	NM_001164508.2(NEB):c.24477_24480dup (p.Ser8161delinsTyrTer)	Pathogenic
2817523	NM_001164508.2(NEB):c.24683_24684del (p.Lys8228fs)	Pathogenic
432817	NM_001164508.2(NEB):c.24588C>G (p.Tyr8196Ter)	Pathogenic
506284	NM_001164508.2(NEB):c.22144A>C (p.Thr7382Pro)	Pathogenic
859754	NM_001164508.2(NEB):c.22312_22315dup (p.Thr7439fs)	Pathogenic
918157	NM_001164508.2(NEB):c.22831C>T (p.Arg7611Ter)	Pathogenic
968758	NM_001164508.2(NEB):c.22645G>T (p.Glu7549Ter)	Pathogenic
1526921	GRCh37/hg19 2q23.3(chr2:150606201-153038451)	Likely pathogenic
1724747	NM_001164508.2(NEB):c.22315dup (p.Thr7439fs)	Likely pathogenic
1724779	NM_001164508.2(NEB):c.22294_22295insCAGATTTA (p.Lys7432fs)	Likely pathogenic
1725467	NM_001164508.2(NEB):c.22804A>T (p.Lys7602Ter)	Likely pathogenic
1994238	NM_001164508.2(NEB):c.24301-1G>T	Likely pathogenic
3584397	NM_001164508.2(NEB):c.25201dup (p.Ser8401fs)	Likely pathogenic
3776963	NM_001164508.2(NEB):c.22924del (p.Tyr7642fs)	Likely pathogenic
4814762	NM_001164508.2(NEB):c.23668del (p.Ala7889_Ile7890insTer)	Likely pathogenic
4814765	NM_001164508.2(NEB):c.24276dup (p.His8093fs)	Likely pathogenic
554692	NM_001164508.2(NEB):c.23929-2A>C	Likely pathogenic
558061	NM_001164508.2(NEB):c.23834C>A (p.Ser7945Ter)	Likely pathogenic

SpliceAI

7681 predictions. Top by Δscore:

Variant	Effect	Δscore
2:151410399:C:CA	acceptor_gain	1.0000
2:151410524:CCAG:C	donor_loss	1.0000
2:151410525:CAG:C	donor_loss	1.0000
2:151410526:AG:A	donor_loss	1.0000
2:151410527:GGT:G	donor_loss	1.0000
2:151410528:GTG:G	donor_loss	1.0000
2:151411249:T:TA	acceptor_gain	1.0000
2:151411256:TAAGT:T	acceptor_loss	1.0000
2:151411257:A:AG	acceptor_gain	1.0000
2:151411257:AAGTC:A	acceptor_gain	1.0000
2:151411258:A:G	acceptor_gain	1.0000
2:151411258:AGTC:A	acceptor_gain	1.0000
2:151411259:G:GG	acceptor_gain	1.0000
2:151411259:GT:G	acceptor_gain	1.0000
2:151411259:GTC:G	acceptor_gain	1.0000
2:151411259:GTCG:G	acceptor_gain	1.0000
2:151411259:GTCGT:G	acceptor_gain	1.0000
2:151411336:AAG:A	donor_gain	1.0000
2:151411337:AG:A	donor_gain	1.0000
2:151411337:AGG:A	donor_loss	1.0000
2:151411338:GG:G	donor_gain	1.0000
2:151411338:GGTA:G	donor_loss	1.0000
2:151411339:G:GG	donor_gain	1.0000
2:151416552:GTTTT:G	acceptor_loss	1.0000
2:151416553:TTTTT:T	acceptor_loss	1.0000
2:151416554:TTTTC:T	acceptor_loss	1.0000
2:151416555:TTTCA:T	acceptor_loss	1.0000
2:151416556:TTCA:T	acceptor_loss	1.0000
2:151416557:TCA:T	acceptor_loss	1.0000
2:151416559:A:AG	acceptor_gain	1.0000

AlphaMissense

16306 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:151420236:T:A	W184R	1.000
2:151420236:T:C	W184R	1.000
2:151423013:T:A	W253R	1.000
2:151423013:T:C	W253R	1.000
2:151428813:T:A	N272K	1.000
2:151428813:T:G	N272K	1.000
2:151428821:T:C	L275S	1.000
2:151428821:T:G	L275W	1.000
2:151428838:G:A	G281R	1.000
2:151428838:G:C	G281R	1.000
2:151428839:G:A	G281E	1.000
2:151428841:T:C	F282L	1.000
2:151428842:T:C	F282S	1.000
2:151428842:T:G	F282C	1.000
2:151428843:T:A	F282L	1.000
2:151428843:T:G	F282L	1.000
2:151428875:C:A	A293D	1.000
2:151428878:T:C	F294S	1.000
2:151428886:T:A	W297R	1.000
2:151428886:T:C	W297R	1.000
2:151428888:G:C	W297C	1.000
2:151428888:G:T	W297C	1.000
2:151428896:T:C	L300S	1.000
2:151428906:T:A	N303K	1.000
2:151428906:T:G	N303K	1.000
2:151428907:T:C	F304L	1.000
2:151428908:T:C	F304S	1.000
2:151428909:T:A	F304L	1.000
2:151428909:T:G	F304L	1.000
2:151433095:A:T	K315I	1.000

dbSNP variants (sampled 300 via entrez): RS1000034309 (2:151413287 C>T), RS1000042298 (2:151420096 C>A,T), RS1000050080 (2:151529885 T>A,C), RS1000091357 (2:151430462 C>T), RS1000093799 (2:151530081 G>T), RS1000098846 (2:151480084 C>T), RS1000107124 (2:151522961 T>G), RS1000109867 (2:151450149 TC>T,TCC), RS1000115985 (2:151510145 C>T), RS1000124462 (2:151473445 T>G), RS1000145984 (2:151529772 C>T), RS1000149557 (2:151480380 T>C), RS1000155500 (2:151426415 C>T), RS1000180829 (2:151511462 G>A), RS1000188352 (2:151505200 G>A,C,T)

Disease associations

OMIM: gene MIM:608952 | disease phenotypes: MIM:256030, MIM:619334

GenCC curated gene-disease

Mondo (5): nemaline myopathy 2 (MONDO:0009725), strabismus (MONDO:0003432), arthrogryposis multiplex congenita 6 (MONDO:0030281), nebulin-related early-onset distal myopathy (MONDO:0018371), nemaline myopathy (MONDO:0018958)

Orphanet (2): Autosomal recessive distal nebulin myopathy (Orphanet:399103), Nemaline myopathy (Orphanet:607)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290
D013285	Strabismus	C10.292.562.887; C11.590.810
C538349	Nemaline Myopathy 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725140 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.46	Kd	3462	nM	CHEMBL5653589
5.46	ED50	3462	nM	CHEMBL5653589
5.23	IC50	5940	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149227: Binding affinity to human RIF1 incubated for 45 mins by Kinobead based pull down assay	kd	3.4625	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178707: Inhibition of RIF1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	5.9400	uM

CTD chemical–gene interactions

53 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
trichostatin A	decreases expression, increases expression	2
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	2
perfluorooctane sulfonic acid	decreases expression	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	increases expression	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Tretinoin	decreases expression	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
biochanin A	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
tamibarotene	decreases expression	1
corosolic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
torcetrapib	increases expression	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652269	Binding	Binding affinity to human RIF1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TJ01	HAP1 RIF1 (-) 1	Cancer cell line	Male
CVCL_TJ02	HAP1 RIF1 (-) 2	Cancer cell line	Male
CVCL_TJ03	HAP1 RIF1 (-) 3	Cancer cell line	Male
CVCL_TJ04	HAP1 RIF1 (-) 4	Cancer cell line	Male
CVCL_TJ05	HAP1 RIF1 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00461656	PHASE4	COMPLETED	Povidone-iodine Antisepsis for Strabismus Surgery
NCT01901588	PHASE4	COMPLETED	Efficacy of Single-Shot Dexmedetomidine Versus Placebo in Preventing Pediatric Emergence Delirium in Strabismus Surgery
NCT02379546	PHASE4	COMPLETED	The Effect of Anaesthesia Depth on Oculo-cardiac Reflex
NCT03349515	PHASE4	COMPLETED	The Effect of Povidone-iodine Ophthalmic Surgical Prep Solution on Respiration in Children Undergoing Strabismus Surgery With General Anesthesia.
NCT04549844	PHASE4	UNKNOWN	Peribulbar Block for Prevention of Oculocardiac Reflex
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06560268	PHASE4	NOT_YET_RECRUITING	Low Flow Anesthesia in Children Undergoing Strabismus Surgery
NCT00000128	PHASE3	UNKNOWN	A Trial of Bifocals in Myopic Children With Esophoria
NCT00001864	PHASE3	COMPLETED	Amblyopia (Lazy Eye) Treatment Study
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
NCT01584843	PHASE3	COMPLETED	Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Strabismus
NCT04060771	PHASE3	UNKNOWN	Post-Operative Nausea and Vomiting in Children Submitted to Strabismus Surgery
NCT06863675	PHASE3	NOT_YET_RECRUITING	Highly Aspherical Lenslet (HAL) and Binocular Vision (BV) Disorders [HALT X(T) Study]
NCT00478907	PHASE2	COMPLETED	Prevention of Complications of Eye Surgery
NCT06689943	PHASE2	NOT_YET_RECRUITING	Pain After Strabismus Surgery
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
NCT00917982	PHASE1	UNKNOWN	The Effect of Vision Therapy/Orthoptic on Motor & Sensory Status of the 3 to 7 Years Old Strabismic Patients
NCT02246556	PHASE1	TERMINATED	Dichoptic Virtual Reality Therapy for Amblyopia in Adults
NCT01616108	PHASE2/PHASE3	UNKNOWN	Bupivacaine Injection of Eye Muscles to Treat Strabismus
NCT00001143	Not specified	COMPLETED	Development of the Eye Motor System During the First 7 Months of Life in Infants With and Without a Family History of Cross-Eye
NCT00001861	Not specified	COMPLETED	Screening for Studies on Nystagmus and Strabismus
NCT00304577	Not specified	COMPLETED	Bilateral Recession or Unilateral Recession-Resection as Surgery for Infantile Esotropia
NCT00338559	Not specified	COMPLETED	Does LMA Instead of ET Tube Affect Incidence of Postoperative Vomiting in Children Undergoing Strabismus Correction?
NCT00535938	Not specified	COMPLETED	MDs on Botox Utility (MOBILITY)
NCT00559234	Not specified	COMPLETED	Potential Research Participants for Future Studies of Inherited Eye Diseases
NCT01109459	Not specified	COMPLETED	Multimodal Physician Intervention to Detect Amblyopia
NCT01430247	Not specified	COMPLETED	Vision Screening for the Detection of Amblyopia
NCT01512355	Not specified	COMPLETED	The Effect of Dexmedetomidine on Decreasing Emergence Agitation and Delirium in Pediatric Patients Undergoing Strabismus Surgery
NCT01608828	Not specified	COMPLETED	Assessing the Functional and Psychosocial Impact of Strabismus in Asian Children Using the AS-20 and IXTQ Questionnaires
NCT01706991	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner
NCT01726842	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner
NCT01791946	Not specified	COMPLETED	Binocular Treatment of Amblyopia Before and After Strabismus Surgery
NCT01812044	Not specified	COMPLETED	Postoperative Subtenons Anesthesia for Postoperative Pain in Pediatric Strabismus Surgery
NCT01832883	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner
NCT02113709	Not specified	UNKNOWN	Determining the Efficacy of Full-time Occlusion Therapy in Severe Amblyopia at Different Ages
NCT02152787	Not specified	UNKNOWN	Comparison of Propofol 1mg/kg and Propofol 0.5mg/kg for Prevention of Emergence Agitation in Children Undergoing Strabismus Surgery During Sevoflurane Anesthesia
NCT02228070	Not specified	COMPLETED	Strabismus Measurements Using Automated 3D Video Oculography
NCT02236351	Not specified	UNKNOWN	New Pediatric Patching Method to Improve Compliance
NCT02360969	Not specified	COMPLETED	Effect of Neuromuscular Blockade on the Oculomotor by Not Squinting Child
NCT02454920	Not specified	COMPLETED	Measurement of Insertion of Extraocular Muscles Using Anterior Segment Optical Coherence Tomography