CIRSR

Summary

CIRSR (corepressor of RBPJ and splicing regulator, HGNC:24217) is a protein-coding gene on chromosome 2q31.1, encoding Corepressor of RBPJ and splicing regulator (Q86X95). May modulate splice site selection during alternative splicing of pre-mRNAs. It is a selective cancer dependency (DepMap: 26.7% of cell lines).

Enables histone deacetylase binding activity; protein kinase binding activity; and transcription corepressor activity. Acts upstream of or within negative regulation of transcription by RNA polymerase II. Located in centrosome and nuclear speck. Part of protein-containing complex.

Source: NCBI Gene 9541 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 47 total
• Cancer dependency (DepMap): dependent in 26.7% of screened cell lines
• MANE Select transcript: NM_004882

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24217
Approved symbol	CIRSR
Name	corepressor of RBPJ and splicing regulator
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	CIR
Ensembl gene	ENSG00000138433
Ensembl biotype	protein_coding
OMIM	605228
Entrez	9541

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 retained_intron

ENST00000342016, ENST00000377973, ENST00000461454, ENST00000464393, ENST00000472169, ENST00000971389

RefSeq mRNA: 1 — MANE Select: NM_004882 NM_004882

CCDS: CCDS2256

Canonical transcript exons

ENST00000342016 — 10 exons

Exon	Start	End
ENSE00001016378	174395551	174395712
ENSE00001811467	174348022	174349172
ENSE00003399080	174378923	174379040
ENSE00003475005	174350660	174350745
ENSE00003521395	174380804	174380814
ENSE00003542997	174380202	174380250
ENSE00003572563	174351619	174351725
ENSE00003589217	174381704	174381777
ENSE00003650903	174387685	174387779
ENSE00003671783	174380651	174380715

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.6314 / max 1377.9470, expressed in 1795 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31863	35.2456	1795
31860	0.3858	155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	97.30	gold quality
monocyte	CL:0000576	95.50	gold quality
calcaneal tendon	UBERON:0003701	95.37	gold quality
tendon	UBERON:0000043	95.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.01	gold quality
mononuclear cell	CL:0000842	94.93	gold quality
leukocyte	CL:0000738	94.77	gold quality
sural nerve	UBERON:0015488	94.08	gold quality
right uterine tube	UBERON:0001302	93.80	gold quality
right lung	UBERON:0002167	92.99	gold quality
mucosa of stomach	UBERON:0001199	92.97	gold quality
skin of leg	UBERON:0001511	92.75	gold quality
blood	UBERON:0000178	92.62	gold quality
skin of abdomen	UBERON:0001416	92.60	gold quality
body of pancreas	UBERON:0001150	92.14	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.82	gold quality
tibial nerve	UBERON:0001323	91.77	gold quality
granulocyte	CL:0000094	91.75	gold quality
tibial artery	UBERON:0007610	91.72	gold quality
popliteal artery	UBERON:0002250	91.71	gold quality
descending thoracic aorta	UBERON:0002345	91.67	gold quality
left ovary	UBERON:0002119	91.57	gold quality
rectum	UBERON:0001052	91.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.50	gold quality
endocervix	UBERON:0000458	91.16	gold quality
spleen	UBERON:0002106	91.14	gold quality
adenohypophysis	UBERON:0002196	91.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.26
E-CURD-97	no	946.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting CIRSR, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-513B-3P	98.76	68.12	1577

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• identified as a PAP-1 binding protein and as a splicing factor (PMID:15652350)
• three SNPs (corepressor interacting with RBPJ 1 (CIR1) rs13009079T>C, ribonucleotide reductase M1 (RRM1) rs1465952T>C and solute carrier family 38, member 4 (SLC38A4) rs2429467C>T), may play a role in the pathogenesis of lung cancer (PMID:27587543)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cir1	ENSDARG00000099733
mus_musculus	Cir1	ENSMUSG00000041777
rattus_norvegicus	Cir1	ENSRNOG00000018719
drosophila_melanogaster	CG6843	FBGN0036827
caenorhabditis_elegans	cir-1	WBGENE00018892

Protein

Protein identifiers

Corepressor of RBPJ and splicing regulator — Q86X95 (reviewed: Q86X95)

Alternative names: CBF1-interacting corepressor, Corepressor interacting with RBPJ 1, Recepin

All UniProt accessions (2): Q86X95, H3BLY3

UniProt curated annotations — full annotation on UniProt →

Function. May modulate splice site selection during alternative splicing of pre-mRNAs. Regulates transcription and acts as corepressor for RBPJ. Recruits RBPJ to the Sin3-histone deacetylase complex (HDAC). Required for RBPJ-mediated repression of transcription.

Subunit / interactions. Interacts with RP9, SNW1, SFRS1, SFRS2,U2AF1, RBPJ, SAP30, HDAC2, NKAP and NEK6. Interacts with Epstein-Barr virus RPMS1. Component of the histone deacetylase complex. Component of the Notch corepressor complex. Interacts with NKAPL.

Subcellular location. Nucleus speckle. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Highly expressed in heart, brain, placenta, liver, skeletal muscle and pancreas.

Post-translational modifications. Phosphorylated by NEK6.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q86X95-1	1	yes
Q86X95-2	2

RefSeq proteins (1): NP_004873* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019339	CIR_N_dom	Domain
IPR040014	CIR1	Family

Pfam: PF10197

UniProt features (25 total): compositionally biased region 8, region of interest 4, sequence conflict 4, cross-link 2, splice variant 2, short sequence motif 2, chain 1, modified residue 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6ZYM	ELECTRON MICROSCOPY	3.4
8I0W	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86X95-F1	60.12	0.12

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 (3): 202, 79, 340

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 127 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, IVANOVA_HEMATOPOIESIS_MATURE_CELL, KYNG_DNA_DAMAGE_DN, RIZKI_TUMOR_INVASIVENESS_3D_DN, SHIRAISHI_PLZF_TARGETS_UP, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, CHEOK_RESPONSE_TO_MERCAPTOPURINE_DN, GOCC_CENTROSOME, GOBP_RNA_SPLICING, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_EMBRYO_DEVELOPMENT, URS_ADIPOCYTE_DIFFERENTIATION_UP, DANG_BOUND_BY_MYC

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), in utero embryonic development (GO:0001701), mRNA processing (GO:0006397), RNA splicing (GO:0008380), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): transcription corepressor activity (GO:0003714), protein kinase binding (GO:0019901), histone deacetylase binding (GO:0042826), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), centrosome (GO:0005813), nuclear speck (GO:0016607), protein-containing complex (GO:0032991), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of DNA-templated transcription	2
RNA processing	2
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
chordate embryonic development	1
mRNA metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription coregulator activity	1
kinase binding	1
enzyme binding	1
intracellular membrane-bounded organelle	1
centriole	1
microtubule organizing center	1
nuclear ribonucleoprotein granule	1
cellular_component	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CIRSR	RBPJ	Q06330	872
CIRSR	SAP30	O75446	781
CIRSR	NENF	Q9UMX5	780
CIRSR	CTBP1	Q13363	682
CIRSR	CTBP2	P56545	662
CIRSR	SNW1	Q13573	647
CIRSR	NCOR2	Q9Y618	606
CIRSR	SPEN	Q96T58	560
CIRSR	HDAC2	Q92769	558
CIRSR	HDAC1	Q13547	552
CIRSR	NOTCH1	P46531	516
CIRSR	NCOR1	O75376	515
CIRSR	RBBP8	Q99708	493
CIRSR	NRDE2	Q9H7Z3	476
CIRSR	NKAP	Q8N5F7	448

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CIR1	U2AF1	psi-mi:“MI:0915”(physical association)	0.590
U2AF1	CIR1	psi-mi:“MI:0915”(physical association)	0.590
CIR1	U2AF1	psi-mi:“MI:0407”(direct interaction)	0.590
CEP76	CIR1	psi-mi:“MI:0915”(physical association)	0.560
SRSF2	CIR1	psi-mi:“MI:0403”(colocalization)	0.540
CIR1	SRSF2	psi-mi:“MI:0915”(physical association)	0.540
SRSF2	CIR1	psi-mi:“MI:0915”(physical association)	0.540
SRSF1	CIR1	psi-mi:“MI:0915”(physical association)	0.510
RBPJ	CIR1	psi-mi:“MI:0915”(physical association)	0.440
CIR1	RBPJ	psi-mi:“MI:0403”(colocalization)	0.440
CIR1	HIST2H2BF	psi-mi:“MI:0915”(physical association)	0.400
CIR1	E7	psi-mi:“MI:0915”(physical association)	0.370
CIR1		psi-mi:“MI:0915”(physical association)	0.370
CIR1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
CIR1	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
SAP30	CIR1	psi-mi:“MI:0915”(physical association)	0.370
HDAC2	CIR1	psi-mi:“MI:0915”(physical association)	0.370
ECE1	CIR1	psi-mi:“MI:0915”(physical association)	0.370
CIR1	ECE1	psi-mi:“MI:0915”(physical association)	0.370
AGO3		psi-mi:“MI:0914”(association)	0.350
FANCI	FAAP20	psi-mi:“MI:0914”(association)	0.350
HTRA4	PSMD12	psi-mi:“MI:0914”(association)	0.350
HTRA4	ATOX1	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): CEP76 (Two-hybrid), CIR1 (Affinity Capture-MS), CIR1 (Affinity Capture-MS), CCNYL1 (Affinity Capture-MS), UBR3 (Affinity Capture-MS), GCA (Affinity Capture-MS), BTBD1 (Affinity Capture-MS), DCAF10 (Affinity Capture-MS), CDCA3 (Affinity Capture-MS), RBM12 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), EPHA2 (Affinity Capture-MS), CIR1 (Affinity Capture-MS), CIR1 (Affinity Capture-Western), SNW1 (Two-hybrid)

ESM2 similar proteins: A2AQ19, B2GV05, O54941, O55047, O95232, P08621, P09406, P23588, P50502, P52756, P97762, Q07866, Q08CW1, Q13123, Q1ECX4, Q1RMR2, Q1RMU5, Q32KT0, Q3SX41, Q56A18, Q5NVI3, Q5R8W6, Q5RAD5, Q5RF31, Q5SRX1, Q5SUF2, Q5U2T8, Q5U2U0, Q5ZI03, Q62376, Q66HG8, Q66II8, Q6PH81, Q7TNC4, Q86UE8, Q86X95, Q8BGD9, Q8C0V0, Q8TA86, Q90ZY6

Diamond homologs: Q5U2T8, Q5ZI03, Q86X95, Q9DA19

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RBPJ	up-regulates	CIR1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1560 predictions. Top by Δscore:

Variant	Effect	Δscore
2:174349169:TTTC:T	acceptor_gain	1.0000
2:174349170:TTC:T	acceptor_gain	1.0000
2:174349171:TC:T	acceptor_gain	1.0000
2:174349172:CC:C	acceptor_gain	1.0000
2:174349173:C:CC	acceptor_gain	1.0000
2:174349173:CTGTA:C	acceptor_loss	1.0000
2:174349179:T:TC	acceptor_gain	1.0000
2:174350743:CTC:C	acceptor_gain	1.0000
2:174351617:A:AG	donor_loss	1.0000
2:174351618:CCTG:C	donor_loss	1.0000
2:174351721:TGGCC:T	acceptor_gain	1.0000
2:174351723:GCCC:G	acceptor_loss	1.0000
2:174351724:CC:C	acceptor_gain	1.0000
2:174351725:CC:C	acceptor_gain	1.0000
2:174351726:C:CC	acceptor_gain	1.0000
2:174351726:CTGTT:C	acceptor_loss	1.0000
2:174351727:T:C	acceptor_loss	1.0000
2:174378917:GCCTA:G	donor_loss	1.0000
2:174378918:CCTA:C	donor_loss	1.0000
2:174378919:CTA:C	donor_loss	1.0000
2:174378920:TACC:T	donor_loss	1.0000
2:174378922:CCT:C	donor_loss	1.0000
2:174379038:AACC:A	acceptor_loss	1.0000
2:174379039:ACCTG:A	acceptor_loss	1.0000
2:174379041:CTGAG:C	acceptor_loss	1.0000
2:174379042:T:C	acceptor_loss	1.0000
2:174380258:A:AC	acceptor_gain	1.0000
2:174380258:A:C	acceptor_gain	1.0000
2:174380269:G:C	acceptor_gain	1.0000
2:174380644:T:TA	donor_gain	1.0000

AlphaMissense

3032 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:174349167:A:G	L228S	1.000
2:174350663:A:G	L225P	1.000
2:174350666:A:G	L224P	1.000
2:174350690:A:G	L216P	1.000
2:174350699:A:G	L213S	1.000
2:174350702:A:G	F212S	1.000
2:174351689:A:C	M174R	1.000
2:174351689:A:G	M174T	1.000
2:174351701:A:G	L170P	1.000
2:174378978:A:C	C143W	1.000
2:174378979:C:A	C143F	1.000
2:174378979:C:G	C143S	1.000
2:174378979:C:T	C143Y	1.000
2:174378980:A:C	C143G	1.000
2:174378980:A:G	C143R	1.000
2:174378980:A:T	C143S	1.000
2:174378988:T:A	D140V	1.000
2:174378988:T:C	D140G	1.000
2:174378988:T:G	D140A	1.000
2:174378989:C:G	D140H	1.000
2:174378993:G:C	N138K	1.000
2:174378993:G:T	N138K	1.000
2:174378997:A:T	V137D	1.000
2:174378999:A:C	H136Q	1.000
2:174378999:A:T	H136Q	1.000
2:174379001:G:C	H136D	1.000
2:174379001:G:T	H136N	1.000
2:174379003:C:A	G135V	1.000
2:174379003:C:T	G135D	1.000
2:174379004:C:A	G135C	1.000

dbSNP variants (sampled 300 via entrez): RS1000022845 (2:174375880 A>T), RS1000053905 (2:174396494 G>A,T), RS1000054265 (2:174372503 A>C), RS1000070744 (2:174365440 A>C), RS1000265773 (2:174393236 A>C,G), RS1000314693 (2:174357331 T>C), RS1000363044 (2:174372135 G>C), RS1000379072 (2:174388817 T>A,C), RS1000387836 (2:174395386 C>A), RS1000601111 (2:174355629 C>G), RS1000653352 (2:174355960 G>A), RS1000664344 (2:174360447 G>C), RS1000670688 (2:174356913 A>C), RS1000720432 (2:174393604 G>A,C), RS1000923832 (2:174369259 A>G)

Disease associations

OMIM: gene MIM:605228 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005829_22	Hand grip strength	2.000000e-10
GCST005830_93	Hand grip strength	9.000000e-13
GCST006079_2	Accelerometer-based physical activity measurement (fraction of time with accelerations >425 milli-gravities)	5.000000e-09
GCST007576_97	Chronotype	1.000000e-11
GCST010244_352	Triglyceride levels	4.000000e-08
GCST010988_194	Adult body size	8.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006941	grip strength measurement
EFO:0008002	physical activity measurement
EFO:0008328	chronotype measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
zinc chromate	increases abundance, increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Glyphosate	increases expression	1
Air Pollutants	decreases expression	1
Air Pollutants, Occupational	increases expression	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Ribonucleotides	affects binding	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7MK	Ubigene A-549 CIR1 KO	Cancer cell line	Male
CVCL_D8J1	Ubigene HCT 116 CIR1 KO	Cancer cell line	Male
CVCL_D9C1	Ubigene HEK293 CIR1 KO	Transformed cell line	Female
CVCL_E0A7	Ubigene HeLa CIR1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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