ZBTB8OS

Summary

ZBTB8OS (zinc finger and BTB domain containing 8 opposite strand, HGNC:24094) is a protein-coding gene on chromosome 1p35.1, encoding tRNA-splicing ligase-activating factor archease (Q8IWT0). Activation factor of RTCB, the catalytic subunit of the tRNA-splicing ligase complex (tRNA-LC), which is involved in the enzyme-dependent maturation of intron-containing pre-tRNAs. It is a common-essential gene (DepMap: required in 98.6% of cancer cell lines).

Predicted to enable metal ion binding activity. Involved in tRNA splicing, via endonucleolytic cleavage and ligation. Part of tRNA-splicing ligase complex.

Source: NCBI Gene 339487 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 29 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_178547

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24094
Approved symbol	ZBTB8OS
Name	zinc finger and BTB domain containing 8 opposite strand
Location	1p35.1
Locus type	gene with protein product
Status	Approved
Aliases	ARCH
Ensembl gene	ENSG00000176261
Ensembl biotype	protein_coding
OMIM	615891
Entrez	339487

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000341885, ENST00000373501, ENST00000373506, ENST00000436661, ENST00000465588, ENST00000466361, ENST00000467652, ENST00000468695, ENST00000473294, ENST00000473383, ENST00000476493, ENST00000479075, ENST00000483138, ENST00000492007, ENST00000498691, ENST00000899477, ENST00000899478, ENST00000899479, ENST00000899480, ENST00000933118, ENST00000933119, ENST00000933120, ENST00000933121, ENST00000933122, ENST00000933123, ENST00000933124, ENST00000933125

RefSeq mRNA: 24 — MANE Select: NM_178547 NM_001308135, NM_001308136, NM_001308137, NM_001308138, NM_001308139, NM_001308140, NM_001308141, NM_001330475, NM_001366255, NM_001366256, NM_001366257, NM_001366258, NM_001366259, NM_001366260, NM_001366263, NM_001366264, NM_001366265, NM_001366266, NM_001366267, NM_001366268, NM_001366269, NM_001366270, NM_001366271, NM_178547

CCDS: CCDS365, CCDS76134, CCDS81292

Canonical transcript exons

ENST00000468695 — 7 exons

Exon	Start	End
ENSE00001326521	32650433	32650550
ENSE00001826660	32620820	32621948
ENSE00003470229	32633645	32633727
ENSE00003589102	32627508	32627544
ENSE00003621651	32633951	32634072
ENSE00003681847	32631827	32631879
ENSE00003738042	32634768	32634792

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 95.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.0131 / max 1595.5053, expressed in 1808 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11546	39.0297	1804
11547	0.9835	578

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.80	gold quality
mucosa of transverse colon	UBERON:0004991	95.80	gold quality
left ventricle myocardium	UBERON:0006566	95.74	gold quality
leukocyte	CL:0000738	95.67	gold quality
bone marrow cell	CL:0002092	95.12	gold quality
islet of Langerhans	UBERON:0000006	95.10	gold quality
rectum	UBERON:0001052	94.87	gold quality
calcaneal tendon	UBERON:0003701	94.80	gold quality
adenohypophysis	UBERON:0002196	94.77	gold quality
body of pancreas	UBERON:0001150	94.54	gold quality
kidney epithelium	UBERON:0004819	94.40	gold quality
ileal mucosa	UBERON:0000331	94.26	gold quality
colonic epithelium	UBERON:0000397	94.13	gold quality
vermiform appendix	UBERON:0001154	94.09	gold quality
pancreas	UBERON:0001264	94.07	gold quality
granulocyte	CL:0000094	94.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.88	gold quality
pituitary gland	UBERON:0000007	93.79	gold quality
gastrocnemius	UBERON:0001388	93.75	gold quality
body of stomach	UBERON:0001161	93.69	gold quality
muscle of leg	UBERON:0001383	93.66	gold quality
left coronary artery	UBERON:0001626	93.44	gold quality
descending thoracic aorta	UBERON:0002345	93.44	gold quality
lower esophagus	UBERON:0013473	93.41	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.41	gold quality
transverse colon	UBERON:0001157	93.32	gold quality
epithelial cell of pancreas	CL:0000083	93.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.23	gold quality
thoracic aorta	UBERON:0001515	93.22	gold quality
ascending aorta	UBERON:0001496	93.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting ZBTB8OS, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-10393-5P	99.65	68.01	1368

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• archease (also called ZBTB8OS), a protein of unknown function, is required for full activity of the human tRNA ligase complex and, in cooperation with DDX1, facilitates the formation of an RTCB-guanylate intermediate central to mammalian RNA ligation (PMID:24870230)
• RTCB, the catalytic subunit of the tRNA ligase complex, and its co-factor archease mediate XBP1 mRNA splicing both in vitro and in vivo. (PMID:25378478)
• ARCH mutation is associated with chronic myelomonocytic leukemia. (PMID:26648538)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	zbtb8os	ENSDARG00000016368
mus_musculus	Zbtb8os	ENSMUSG00000057572
rattus_norvegicus	Zbtb8os	ENSRNOG00000008226
drosophila_melanogaster	Archease	FBGN0289108
caenorhabditis_elegans	arch-1	WBGENE00016621

Protein

Protein identifiers

tRNA-splicing ligase-activating factor archease — Q8IWT0 (reviewed: Q8IWT0)

Alternative names: Zinc finger and BTB domain-containing opposite strand protein 8

All UniProt accessions (12): A0A087WTK6, A0A087WUU3, A0A087WW18, A0A087X0V4, A0A087X1H4, A0A8C8MQ05, A8K0B5, D3DPQ2, Q8IWT0, F6SII6, H7C3R6, S4R426

UniProt curated annotations — full annotation on UniProt →

Function. Activation factor of RTCB, the catalytic subunit of the tRNA-splicing ligase complex (tRNA-LC), which is involved in the enzyme-dependent maturation of intron-containing pre-tRNAs. Functions downstream of the tRNA-splicing endonuclease that removes introns, ligating the two generated halves via phosphodiester bond formation. Catalyzes the GTP-dependent activation of RTCB, both proteins forming a composite active site coordinating GTP and metal ions to enable the guanylylation of RTCB a prerequisite to undergo multiple catalytic cycles. Also required for the activation of RTCB in non-canonical, spliceosome-independent, cytoplasmic splicing of XBP1 mRNAs during the unfolded protein response (UPR). Upon endoplasmic reticulum (ER) stress, the endoribonuclease IRE1/ERN1 excises a short intron, generating free exon ends that are aligned by RNA-intrinsic, zipper-like stem-loop structures. These exon ends are then recognized and ligated by RTCB. This splicing event yields the active XBP1s transcription factor, which induces genes required to resolve protein folding defects in the endoplasmic reticulum.

Subunit / interactions. Monomeric. Could also form homodimers. Associates, as a monomer, with the tRNA-splicing ligase complex composed of the catalytic subunit RTCB and the accessory proteins DDX1, C2orf49/Ashwin/ASW, FAM98B and RTRAF/CGI-99.

Subcellular location. Cytoplasm. Nucleus.

Cofactor. Binds 1 Mn(2+) ion per subunit. Three Mn(2+) ions are bound in the composite active site formed by RTCB and Archease. Two are exclusively coordinated by RTCB residues and the third one is solely coordinated by ZBTB8OS/Archease residues.

Similarity. Belongs to the archease family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IWT0-1	1	yes
Q8IWT0-2	2
Q8IWT0-3	3

RefSeq proteins (24): NP_001295064, NP_001295065, NP_001295066, NP_001295067, NP_001295068, NP_001295069, NP_001295070, NP_001317404, NP_001353184, NP_001353185, NP_001353186, NP_001353187, NP_001353188, NP_001353189, NP_001353192, NP_001353193, NP_001353194, NP_001353195, NP_001353196, NP_001353197, NP_001353198, NP_001353199, NP_001353200, NP_848642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002804	Archease	Family
IPR023572	Archease_dom	Domain
IPR036820	Archease_dom_sf	Homologous_superfamily

Pfam: PF01951

Catalyzed reactions (Rhea), 1 shown:

• L-histidyl-[RNA ligase] + GTP = N(pros)-(5’-guanosyl-phosphono)-L-histidyl-[RNA ligase] + diphosphate (RHEA:68084)

UniProt features (15 total): sequence conflict 5, binding site 3, splice variant 2, mutagenesis site 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8BTX	X-RAY DIFFRACTION	1.84
5YZ1	X-RAY DIFFRACTION	1.97
8ODO	X-RAY DIFFRACTION	2.2
8ODP	X-RAY DIFFRACTION	2.3
5YZJ	X-RAY DIFFRACTION	2.79
5YZL	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWT0-F1	92.31	0.84

Functional residue map

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

Ligand- & substrate-binding residues (3): 39; 166; 167

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
39	abolishes ability to activate trna ligase activity of rtcb.
144	abolishes ability to activate trna ligase activity of rtcb.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 140 (showing top): E2F_Q4_01, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, E2F_Q3, SOX9_B1, GOBP_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION, USF_01, GOBP_RNA_SPLICING, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, RYTTCCTG_ETS2_B, E2F1_Q3

GO Biological Process (4): RNA splicing, via endonucleolytic cleavage and ligation (GO:0000394), tRNA exon ligation (GO:0000968), tRNA splicing, via endonucleolytic cleavage and ligation (GO:0006388), tRNA processing (GO:0008033)

GO Molecular Function (3): protein guanylyltransferase activity (GO:0044600), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), tRNA-splicing ligase complex (GO:0072669), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
RNA splicing	1
RNA exon ligation	1
tRNA splicing, via endonucleolytic cleavage and ligation	1
RNA splicing, via endonucleolytic cleavage and ligation	1
tRNA processing	1
RNA processing	1
tRNA metabolic process	1
protein guanylylation	1
guanylyltransferase activity	1
cation binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular protein-containing complex	1
catalytic complex	1
protein-containing complex	1

Protein interactions and networks

STRING

604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBTB8OS	RTCB	Q9Y3I0	874
ZBTB8OS	DDX1	Q92499	748
ZBTB8OS	C1orf94	Q6P1W5	646
ZBTB8OS	FAM98B	Q52LJ0	640
ZBTB8OS	RTRAF	Q9Y224	580
ZBTB8OS	RTCA	O00442	547
ZBTB8OS	TRMT1	Q9NXH9	502
ZBTB8OS	THUMPD2	Q9BTF0	496
ZBTB8OS	C2orf49	Q9BVC5	479
ZBTB8OS	ASPHD1	Q5U4P2	431
ZBTB8OS	CMPK1	P30085	408
ZBTB8OS	TSEN54	Q7Z6J9	385
ZBTB8OS	ALDH18A1	P54886	379
ZBTB8OS	TRPT1	Q86TN4	375
ZBTB8OS	GCNT4	Q9P109	370
ZBTB8OS	RSRC1	Q96IZ7	370

IntAct

10 interactions, top by confidence:

A	B	Type	Score
ZBTB8OS	RTCB	psi-mi:“MI:0915”(physical association)	0.500
	ZBTB8OS	psi-mi:“MI:0915”(physical association)	0.490
ZBTB8OS		psi-mi:“MI:0915”(physical association)	0.490
ZBTB8OS	PAGE2	psi-mi:“MI:0915”(physical association)	0.400
ZBTB8OS	FAM98B	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
ZBTB8OS	gcvP2	psi-mi:“MI:0915”(physical association)	0.000
PRKCH	ZBTB8OS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): ZBTB8OS (Affinity Capture-RNA), ZBTB8OS (Affinity Capture-MS), ATP8A2 (Co-fractionation), HSP90B1 (Co-fractionation), PRPF40A (Co-fractionation), ZBTB8OS (Co-fractionation), GPANK1 (Two-hybrid), ZBTB8OS (Affinity Capture-RNA), ZBTB8OS (Affinity Capture-RNA), ZBTB8OS (Affinity Capture-MS), PAGE2 (Affinity Capture-MS), ZBTB8OS (Negative Genetic), ZBTB8OS (Negative Genetic), ZBTB8OS (Affinity Capture-MS), ZBTB8OS (Negative Genetic)

ESM2 similar proteins: A0A0U1WZ18, A4FV08, A4IHW6, C7EXK4, O88958, O97555, O97556, P21856, P31150, P46926, P50395, P50396, P50397, P50398, P50399, P60028, P61221, P61222, P62497, P70704, Q07346, Q0VCX5, Q16HW7, Q17QL1, Q29449, Q2EGP9, Q2YDE7, Q42472, Q42521, Q505B7, Q566V0, Q5R4C7, Q5R8T8, Q5RCE1, Q5U2Q7, Q5ZIZ4, Q61598, Q64422, Q6PA43, Q6Q7J2

Diamond homologs: A1RV54, A3MTM9, B1YCY3, C3MQ89, C3MVY1, C3N5V7, C3NEH3, C3NH78, C4KHI6, C5A6Z1, O27635, O28777, O59205, Q2EGP9, Q2YDE7, Q46D27, Q4JB72, Q505B7, Q54BU9, Q566V0, Q5JCY8, Q60334, Q8IWT0, Q8PWN9, Q8TU10, Q8TYR4, Q8U0N4, Q8ZWP9, Q975L0, Q9UX79, Q9V105, Q9VD92, Q9YFV2, Q9TZN1, Q61DI9, Q9HKC1, Q97A49

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1505 predictions. Top by Δscore:

Variant	Effect	Δscore
1:32633693:C:CT	acceptor_gain	1.0000
1:32633694:A:T	acceptor_gain	1.0000
1:32633964:TTC:T	donor_gain	1.0000
1:32633965:TCT:T	donor_gain	1.0000
1:32650427:A:AC	donor_gain	1.0000
1:32650428:C:CC	donor_gain	1.0000
1:32650428:CT:C	donor_gain	1.0000
1:32650428:CTCA:C	donor_gain	1.0000
1:32650431:A:AC	donor_gain	1.0000
1:32650432:C:CC	donor_gain	1.0000
1:32650432:CA:C	donor_gain	1.0000
1:32650432:CACT:C	donor_gain	1.0000
1:32650439:A:AC	donor_gain	1.0000
1:32650440:C:CC	donor_gain	1.0000
1:32650442:T:TA	donor_gain	1.0000
1:32650443:C:A	donor_gain	1.0000
1:32631876:CTTC:C	acceptor_gain	0.9900
1:32633639:GCTTA:G	donor_loss	0.9900
1:32633640:CTT:C	donor_loss	0.9900
1:32633641:TTA:T	donor_loss	0.9900
1:32633642:T:TG	donor_loss	0.9900
1:32633643:A:AC	donor_gain	0.9900
1:32633643:A:C	donor_loss	0.9900
1:32633643:AC:A	donor_gain	0.9900
1:32633644:C:CC	donor_gain	0.9900
1:32633644:CC:C	donor_gain	0.9900
1:32633693:C:T	acceptor_gain	0.9900
1:32633699:G:GC	acceptor_gain	0.9900
1:32633726:TCC:T	acceptor_loss	0.9900
1:32633728:C:CC	acceptor_gain	0.9900

AlphaMissense

1188 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000032996 (1:32632413 T>G), RS1000069292 (1:32625924 G>A), RS1000078789 (1:32637539 G>C), RS1000235263 (1:32632198 G>A), RS1000339242 (1:32625733 T>C), RS1000476735 (1:32625424 C>T), RS1000840744 (1:32630577 T>C), RS1000908790 (1:32651102 G>A), RS1001080126 (1:32636356 G>C), RS1001100415 (1:32642823 G>A), RS1001243097 (1:32651566 C>A,T), RS1001265347 (1:32652440 C>T), RS1001378153 (1:32630248 C>T), RS1001422758 (1:32646540 A>G), RS1001487736 (1:32645418 C>G,T)

Disease associations

OMIM: gene MIM:615891 | 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: yes

ChEMBL targets (1): CHEMBL5069379 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	3
Valproic Acid	increases methylation, affects expression, increases expression	3
Particulate Matter	affects cotreatment, increases abundance, decreases expression, decreases reaction	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
sodium arsenite	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Vehicle Emissions	decreases reaction, decreases expression	1
Bilirubin	decreases expression	1
Coumestrol	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Estradiol	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Parathion	increases methylation	1
Phthalic Acids	increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Rotenone	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
1-Butanol	affects cotreatment, decreases expression, increases abundance	1
Acrylamide	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5059512	Binding	Proteomics fold change data (SUDHL4 cells, 1h)	Data for DCP probe CCT369260

Clinical trials (associated diseases)

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