ISY1

Summary

ISY1 (ISY1 spliceosome associated protein, HGNC:29201) is a protein-coding gene on chromosome 3q21.3, encoding Pre-mRNA-splicing factor ISY1 homolog (Q9ULR0). Component of the spliceosome C complex required for the selective processing of microRNAs during embryonic stem cell differentiation. It is a common-essential gene (DepMap: required in 99.2% of cancer cell lines).

Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type catalytic step 1 spliceosome and catalytic step 2 spliceosome.

Source: NCBI Gene 57461 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 10 total
• Cancer dependency (DepMap): dependent in 99.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_020701

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29201
Approved symbol	ISY1
Name	ISY1 spliceosome associated protein
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1160, fSAP33
Ensembl gene	ENSG00000240682
Ensembl biotype	protein_coding
OMIM	612764
Entrez	57461

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000273541, ENST00000393292, ENST00000393295, ENST00000471306, ENST00000471497, ENST00000485703, ENST00000496163, ENST00000935181, ENST00000935182, ENST00000935183, ENST00000948146, ENST00000948147, ENST00000948150, ENST00000948151

RefSeq mRNA: 2 — MANE Select: NM_020701 NM_001199469, NM_020701

CCDS: CCDS43149, CCDS56277

Canonical transcript exons

ENST00000393295 — 11 exons

Exon	Start	End
ENSE00001864948	129127415	129130188
ENSE00001937529	129160973	129161063
ENSE00003468061	129134074	129134195
ENSE00003484637	129130550	129130636
ENSE00003510664	129158508	129158559
ENSE00003586025	129145761	129145873
ENSE00003591792	129159154	129159176
ENSE00003602293	129134832	129134954
ENSE00003606788	129156855	129156920
ENSE00003671145	129156633	129156675
ENSE00003689915	129140368	129140485

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.8603 / max 44.5389, expressed in 1209 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44485	30.8567	1822
44486	1.8603	1209

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.88	gold quality
sural nerve	UBERON:0015488	93.91	gold quality
monocyte	CL:0000576	92.95	gold quality
leukocyte	CL:0000738	92.79	gold quality
lymph node	UBERON:0000029	91.18	gold quality
smooth muscle tissue	UBERON:0001135	91.03	gold quality
muscle of leg	UBERON:0001383	91.03	gold quality
gastrocnemius	UBERON:0001388	91.02	gold quality
granulocyte	CL:0000094	90.06	gold quality
thymus	UBERON:0002370	89.93	gold quality
islet of Langerhans	UBERON:0000006	89.79	gold quality
ganglionic eminence	UBERON:0004023	89.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.61	gold quality
upper arm skin	UBERON:0004263	89.50	silver quality
vermiform appendix	UBERON:0001154	89.44	gold quality
blood	UBERON:0000178	89.41	gold quality
gall bladder	UBERON:0002110	89.31	gold quality
ileal mucosa	UBERON:0000331	89.05	gold quality
ectocervix	UBERON:0012249	89.04	gold quality
rectum	UBERON:0001052	88.88	gold quality
stromal cell of endometrium	CL:0002255	88.87	gold quality
body of uterus	UBERON:0009853	88.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.71	gold quality
pancreatic ductal cell	CL:0002079	88.68	silver quality
ventricular zone	UBERON:0003053	88.57	gold quality
esophagus mucosa	UBERON:0002469	88.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.52	gold quality
pancreas	UBERON:0001264	88.51	gold quality
uterine cervix	UBERON:0000002	88.44	gold quality
esophagus	UBERON:0001043	88.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	1193.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting ISY1, 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-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-4722-3P	99.35	65.22	1099

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• Describes the function of yeast Isy1p in pre-mRNA splicing. (PMID:16103217)
• The splicing component ISY1 regulates APE1 in base excision repair. (PMID:31887540)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	isy1	ENSDARG00000063466
mus_musculus	Isy1	ENSMUSG00000030056
rattus_norvegicus	Rab43	ENSRNOG00000037768
drosophila_melanogaster	CG9667	FBGN0037550
caenorhabditis_elegans		WBGENE00009966

Protein

Protein identifiers

Pre-mRNA-splicing factor ISY1 homolog — Q9ULR0 (reviewed: Q9ULR0)

All UniProt accessions (4): Q9ULR0, A8MVI5, D6RC18, H0YA89

UniProt curated annotations — full annotation on UniProt →

Function. Component of the spliceosome C complex required for the selective processing of microRNAs during embryonic stem cell differentiation. Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a. Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively. Required during the transition of embryonic stem cells (ESCs) from the naive to primed state. By enhancing miRNA biogenesis, promotes exit of ESCs from the naive state to an intermediate state of poised pluripotency, which precedes transition to the primed state. Involved in pre-mRNA splicing as component of the spliceosome.

Subunit / interactions. Identified in the spliceosome C complex. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE. Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex. The IB complex does not contain PRPF19. Interacts with CPSF3; this interaction is in an RNA independent manner. Interacts with the microprocessor complex subunits DGCR8 and DROSHA; this interaction is in an RNA dependent manner.

Subcellular location. Nucleus.

Miscellaneous. Based on a readthrough transcript which may produce a ISY1-RAB43 fusion protein.

Similarity. Belongs to the ISY1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9ULR0-3	3	yes
Q9ULR0-1	2, ISY1-RAB43
Q9ULR0-2	1

RefSeq proteins (2): NP_001186398, NP_065752* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009360	Isy1	Family
IPR029012	Helix_hairpin_bin_sf	Homologous_superfamily
IPR037200	Isy1_sf	Homologous_superfamily

Pfam: PF06246

UniProt features (10 total): compositionally biased region 2, modified residue 2, splice variant 2, chain 1, region of interest 1, strand 1, helix 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8C6J	ELECTRON MICROSCOPY	2.8
9FMD	ELECTRON MICROSCOPY	3.3
6ZYM	ELECTRON MICROSCOPY	3.4
8I0W	ELECTRON MICROSCOPY	3.4
8RO2	ELECTRON MICROSCOPY	3.5
5YZG	ELECTRON MICROSCOPY	4.1
6FF7	ELECTRON MICROSCOPY	4.5
7A5P	ELECTRON MICROSCOPY	5
8CH6	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULR0-F1	80.60	0.37

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 (2): 127, 247

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-5696398	Nucleotide Excision Repair
R-HSA-72172	mRNA Splicing
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-73894	DNA Repair
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 148 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, GOBP_MRNA_SPLICE_SITE_RECOGNITION, chr3q21, REACTOME_DNA_REPAIR, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, REACTOME_METABOLISM_OF_RNA, GOCC_U2_TYPE_SPLICEOSOMAL_COMPLEX, GOCC_NUCLEAR_SPECK, GOCC_NUCLEAR_BODY, GOCC_RIBONUCLEOPROTEIN_GRANULE, MARSON_BOUND_BY_FOXP3_UNSTIMULATED

GO Biological Process (5): generation of catalytic spliceosome for second transesterification step (GO:0000350), mRNA 3’-splice site recognition (GO:0000389), mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (8): Prp19 complex (GO:0000974), nucleus (GO:0005634), nucleoplasm (GO:0005654), U2-type catalytic step 1 spliceosome (GO:0071006), catalytic step 2 spliceosome (GO:0071013), post-mRNA release spliceosomal complex (GO:0071014), post-spliceosomal complex (GO:0071020), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3
Nucleotide Excision Repair	1
mRNA Splicing	1
Dengue Virus Infection	1
DNA Repair	1
Processing of Capped Intron-Containing Pre-mRNA	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
spliceosomal complex	3
U5 snRNP	3
RNA processing	2
spliceosomal conformational changes to generate catalytic conformation	1
protein-RNA complex assembly	1
mRNA splice site recognition	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
binding	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
U2-type spliceosomal complex	1
U2 snRNP	1
U6 snRNP	1
catalytic step 1 spliceosome	1
Prp19 complex	1
catalytic complex	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

1152 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISY1	HDHD5	Q9BXW7	656
ISY1	RAB43	Q86YS6	613
ISY1	EFCC1	Q9HA90	581
ISY1	UTP11	Q9Y3A2	538
ISY1	TRPT1	Q86TN4	501
ISY1	XAB2	Q9HCS7	458
ISY1	SF3B2	Q13435	457
ISY1	EIF3A	Q14152	449
ISY1	UQCRB	P14927	417
ISY1	CWC22	Q9HCG8	413
ISY1	A0A0A6YYL6	A0A0A6YYL6	405
ISY1	LSM4	Q9Y4Z0	401
ISY1	HAUS2	Q9NVX0	398
ISY1	HHIPL2	Q6UWX4	398
ISY1	RPL27	P08526	377

IntAct

145 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
PPIE	AQR	psi-mi:“MI:0914”(association)	0.810
PRPF19	AQR	psi-mi:“MI:0914”(association)	0.790
XAB2	ISY1	psi-mi:“MI:0915”(physical association)	0.770
PRPF19	PLRG1	psi-mi:“MI:0914”(association)	0.770
SNRPE	GEMIN2	psi-mi:“MI:0914”(association)	0.770
ISY1	XAB2	psi-mi:“MI:0915”(physical association)	0.770
AQR	ZNF830	psi-mi:“MI:0915”(physical association)	0.760
AQR	ZNF830	psi-mi:“MI:0914”(association)	0.760
AQR	ISY1	psi-mi:“MI:0407”(direct interaction)	0.740
ISY1	AQR	psi-mi:“MI:0914”(association)	0.740
SNW1	AQR	psi-mi:“MI:0914”(association)	0.650
SNRPA1	HTATSF1	psi-mi:“MI:0914”(association)	0.640
DHX8	AHCYL1	psi-mi:“MI:0914”(association)	0.640
SNRPA1	U2SURP	psi-mi:“MI:0914”(association)	0.640
DHX8	ISY1	psi-mi:“MI:0915”(physical association)	0.630
SNRPA1	ISY1	psi-mi:“MI:0407”(direct interaction)	0.590
KDM8	ISY1	psi-mi:“MI:0915”(physical association)	0.560
FAM90A1	ISY1	psi-mi:“MI:0915”(physical association)	0.560
LMO1	ISY1	psi-mi:“MI:0915”(physical association)	0.560
CCNC	ISY1	psi-mi:“MI:0915”(physical association)	0.560
MLH1	ISY1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (267): ISY1 (Affinity Capture-RNA), ISY1 (Affinity Capture-RNA), ISY1 (Affinity Capture-RNA), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), ISY1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVH7, A0A4X1TZW7, A0A5F8MPE6, E1B836, E1C760, E7EXT2, F7AEX0, O74370, O95391, P21374, P51950, Q20716, Q24276, Q24740, Q28E45, Q2F5J3, Q2KI00, Q3B820, Q3KQD1, Q3TGF2, Q3ZBE5, Q45GW3, Q4R4P2, Q502W7, Q569B9, Q5EAW4, Q5RHY1, Q5U4F3, Q5XI37, Q5XIN9, Q5ZIG2, Q69ZQ2, Q6SP97, Q7L590, Q80ZG5, Q8BHJ9, Q8BRC6, Q8CDN8, Q8NCR3, Q8TC29

Diamond homologs: O74370, P0CO36, P0CO37, Q20716, Q4PEZ0, Q4WUJ6, Q51LS1, Q54N41, Q5B423, Q69ZQ2, Q6AYB3, Q6BU51, Q6C9I7, Q753F1, Q7SHY8, Q9ULR0, P21374, Q59R35, Q6CJQ3, Q6FR30

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 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
mRNA Splicing	21	26.5×	1e-22
mRNA Splicing - Major Pathway	40	25.1×	1e-44
Processing of Capped Intron-Containing Pre-mRNA	23	21.7×	1e-22
mRNA Splicing - Minor Pathway	8	20.6×	2e-07
mRNA Polyadenylation	18	18.2×	3e-16
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	5	15.3×	7e-04
RNA Polymerase II Transcription Termination	6	15.2×	1e-04
snRNP Assembly	6	14.6×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	9	56.2×	5e-12
spliceosomal snRNP assembly	7	40.7×	4e-08
mRNA splicing, via spliceosome	35	32.1×	2e-41
RNA splicing, via transesterification reactions	5	31.2×	5e-05
RNA splicing	17	15.0×	3e-13
RNA processing	5	10.9×	4e-03
mRNA processing	9	7.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1848 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129140382:A:G	L135P	1.000
3:129140391:A:T	V132D	1.000
3:129140400:A:C	L129W	1.000
3:129140400:A:G	L129S	1.000
3:129140409:G:T	A126E	1.000
3:129140410:C:G	A126P	1.000
3:129140415:C:A	G124V	1.000
3:129140415:C:T	G124E	1.000
3:129140416:C:G	G124R	1.000
3:129140416:C:T	G124R	1.000
3:129140417:A:C	F123L	1.000
3:129140417:A:T	F123L	1.000
3:129140418:A:C	F123C	1.000
3:129140418:A:G	F123S	1.000
3:129140419:A:G	F123L	1.000
3:129140419:A:T	F123I	1.000
3:129140421:T:C	Y122C	1.000
3:129140422:A:C	Y122D	1.000
3:129140422:A:G	Y122H	1.000
3:129140428:A:G	Y120H	1.000
3:129145800:C:A	W87C	1.000
3:129145800:C:G	W87C	1.000
3:129145801:C:G	W87S	1.000
3:129145802:A:G	W87R	1.000
3:129145802:A:T	W87R	1.000
3:129145822:A:G	L80P	1.000
3:129145827:G:C	N78K	1.000
3:129145827:G:T	N78K	1.000
3:129145836:A:C	D75E	1.000
3:129145836:A:T	D75E	1.000

dbSNP variants (sampled 300 via entrez): RS1000043258 (3:129138940 C>T), RS1000056556 (3:129127664 G>A,C), RS1000164583 (3:129155870 C>T), RS1000230029 (3:129144920 C>A), RS1000241991 (3:129157741 G>A), RS1000325633 (3:129161148 G>T), RS1000389974 (3:129151667 TAA>T), RS1000436465 (3:129132488 C>T), RS1000685052 (3:129155499 T>C), RS1000708086 (3:129145194 T>A,C), RS1000974751 (3:129144438 A>G,T), RS1001133552 (3:129151307 T>C), RS1001341709 (3:129144799 T>A,C), RS1001445979 (3:129152595 G>A), RS1001446239 (3:129158238 A>C)

Disease associations

OMIM: gene MIM:612764 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
cupric oxide	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	increases expression	1
bromovanin	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Copper	decreases expression, affects binding	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Disulfiram	affects binding, decreases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	increases expression, affects cotreatment	1
Ribonucleotides	affects binding	1
Tobacco Smoke Pollution	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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