ISG20L2

Summary

ISG20L2 (interferon stimulated exonuclease gene 20 like 2, HGNC:25745) is a protein-coding gene on chromosome 1q23.1, encoding Interferon-stimulated 20 kDa exonuclease-like 2 (Q9H9L3). 3’-> 5’-exoribonuclease involved in ribosome biogenesis in the processing of the 12S pre-rRNA. It is a common-essential gene (DepMap: required in 97.0% of cancer cell lines).

This gene encodes a 3’-5’ exoribonuclease that may be involved in the processing of the 12S pre-rRNA. Pseudogenes have been identified on chromosomes 6 and 11.

Source: NCBI Gene 81875 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 56 total
• Cancer dependency (DepMap): dependent in 97.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001370150

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25745
Approved symbol	ISG20L2
Name	interferon stimulated exonuclease gene 20 like 2
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12671
Ensembl gene	ENSG00000143319
Ensembl biotype	protein_coding
OMIM	611930
Entrez	81875

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000313146, ENST00000368219, ENST00000469074, ENST00000470713, ENST00000472824, ENST00000496538, ENST00000869316, ENST00000869317, ENST00000869318, ENST00000869319, ENST00000917591, ENST00000917592, ENST00000917593, ENST00000917594, ENST00000917595, ENST00000956727, ENST00000956728

RefSeq mRNA: 4 — MANE Select: NM_001370150 NM_001303095, NM_001370150, NM_001370151, NM_001370152

CCDS: CCDS1153

Canonical transcript exons

ENST00000368219 — 4 exons

Exon	Start	End
ENSE00001419699	156726906	156727769
ENSE00001430889	156721895	156723462
ENSE00001446603	156728415	156728766
ENSE00003550562	156724148	156724348

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 98.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.4811 / max 590.4702, expressed in 1816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15189	17.7843	1795
15191	16.1229	1800
15190	0.3622	167
15192	0.1158	31
15188	0.0553	7
15194	0.0284	9
15193	0.0122	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.31	gold quality
left testis	UBERON:0004533	98.30	gold quality
testis	UBERON:0000473	95.20	gold quality
endothelial cell	CL:0000115	92.53	gold quality
sperm	CL:0000019	92.30	gold quality
amniotic fluid	UBERON:0000173	91.36	gold quality
male germ cell	CL:0000015	91.24	gold quality
islet of Langerhans	UBERON:0000006	91.11	gold quality
esophagus squamous epithelium	UBERON:0006920	91.06	gold quality
lower lobe of lung	UBERON:0008949	90.78	gold quality
epithelium of esophagus	UBERON:0001976	90.64	gold quality
rectum	UBERON:0001052	89.58	gold quality
nipple	UBERON:0002030	89.29	gold quality
blood	UBERON:0000178	89.14	gold quality
smooth muscle tissue	UBERON:0001135	89.03	gold quality
squamous epithelium	UBERON:0006914	88.78	gold quality
ganglionic eminence	UBERON:0004023	88.74	gold quality
palpebral conjunctiva	UBERON:0001812	88.66	gold quality
lymph node	UBERON:0000029	88.63	gold quality
gall bladder	UBERON:0002110	88.63	gold quality
granulocyte	CL:0000094	88.51	gold quality
tonsil	UBERON:0002372	88.47	gold quality
superficial temporal artery	UBERON:0001614	88.46	gold quality
leukocyte	CL:0000738	88.25	gold quality
bone marrow cell	CL:0002092	88.25	gold quality
cortical plate	UBERON:0005343	88.17	gold quality
vermiform appendix	UBERON:0001154	88.11	gold quality
mononuclear cell	CL:0000842	87.96	gold quality
monocyte	CL:0000576	87.95	gold quality
tibia	UBERON:0000979	87.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.41
E-MTAB-6108	no	281.54

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• ISG20L2 is a 3’ to 5’ exoribonuclease involved in ribosome biogenesis at the level of 5.8 S rRNA maturation, more specifically in the processing of the 12 S precursor rRNA. (PMID:18065403)
• miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were significantly negatively correlated with miR-139-3p expression in patients with hepatocellular carcinoma. (PMID:30394818)
• ISG20L2: an RNA nuclease regulating T cell activation. (PMID:37646974)
• Molecular mechanism of human ISG20L2 for the ITS1 cleavage in the processing of 18S precursor ribosomal RNA. (PMID:38153123)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Isg20l2	ENSMUSG00000048039
rattus_norvegicus	Isg20l3	ENSRNOG00000011402
rattus_norvegicus	Isg20l1	ENSRNOG00000037348
rattus_norvegicus	Isg20l3	ENSRNOG00000053601
drosophila_melanogaster	CG12877	FBGN0039544
drosophila_melanogaster	prage	FBGN0283741
caenorhabditis_elegans		WBGENE00004095

Paralogs (5): REXO5 (ENSG00000005189), REXO1 (ENSG00000079313), REXO4 (ENSG00000148300), ISG20 (ENSG00000172183), AEN (ENSG00000181026)

Protein

Protein identifiers

Interferon-stimulated 20 kDa exonuclease-like 2 — Q9H9L3 (reviewed: Q9H9L3)

All UniProt accessions (1): Q9H9L3

UniProt curated annotations — full annotation on UniProt →

Function. 3’-> 5’-exoribonuclease involved in ribosome biogenesis in the processing of the 12S pre-rRNA. Displays a strong specificity for a 3’-end containing a free hydroxyl group.

Subcellular location. Nucleus. Nucleolus.

RefSeq proteins (4): NP_001290024, NP_001357079, NP_001357080, NP_001357081 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR013520	Ribonucl_H	Domain
IPR036397	RNaseH_sf	Homologous_superfamily
IPR037433	ISG20_DEDDh	Domain
IPR047021	REXO1/3/4-like	Family

Pfam: PF00929

UniProt features (23 total): helix 7, strand 6, compositionally biased region 5, region of interest 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7YW5	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9L3-F1	73.61	0.51

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol

MSigDB gene sets: 137 (showing top): GOBP_RIBOSOME_BIOGENESIS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, PUJANA_CHEK2_PCC_NETWORK, BOYAULT_LIVER_CANCER_SUBCLASS_G123_UP, SCHLOSSER_SERUM_RESPONSE_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, EGR1_01, GOMF_EXONUCLEASE_ACTIVITY, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, REACTOME_METABOLISM_OF_RNA, BROWNE_HCMV_INFECTION_14HR_UP

GO Biological Process (3): DNA metabolic process (GO:0006259), RNA processing (GO:0006396), ribosome biogenesis (GO:0042254)

GO Molecular Function (7): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), exonuclease activity (GO:0004527), nucleic acid binding (GO:0003676), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): nucleus (GO:0005634), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
rRNA processing in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
nucleic acid metabolic process	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
ribonucleoprotein complex biogenesis	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1790 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISG20L2	NPM1	P06748	551
ISG20L2	FLAD1	Q8NFF5	455
ISG20L2	MBLAC1	A4D2B0	425
ISG20L2	DEDD	O75618	418
ISG20L2	ERI1	Q8IV48	396
ISG20L2	CDH4	P55283	394
ISG20L2	ATOSA	Q32MH5	394
ISG20L2	ZC3H6	P61129	391
ISG20L2	EXOSC10	Q01780	383
ISG20L2	SLCO6A1	Q86UG4	382
ISG20L2	PIP5K1A	Q99755	374
ISG20L2	DIS3	Q9Y2L1	373
ISG20L2	HSD11B2	P80365	369
ISG20L2	KBTBD4	Q9NVX7	363
ISG20L2	KAAG1	Q9UBP8	355

IntAct

46 interactions, top by confidence:

A	B	Type	Score
CDK16	CCNYL1	psi-mi:“MI:0914”(association)	0.800
EML1	ISG20L2	psi-mi:“MI:0915”(physical association)	0.620
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
H1-4	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
H1-4	RRP8	psi-mi:“MI:0914”(association)	0.530
ISG20L2	CRK	psi-mi:“MI:0915”(physical association)	0.400
SRC	ISG20L2	psi-mi:“MI:0915”(physical association)	0.400
FYN	ISG20L2	psi-mi:“MI:0915”(physical association)	0.400
GRB2	ISG20L2	psi-mi:“MI:0915”(physical association)	0.400
NCK1	ISG20L2	psi-mi:“MI:0915”(physical association)	0.400
PLCG1	ISG20L2	psi-mi:“MI:0915”(physical association)	0.400
ISG20L2	H1-2	psi-mi:“MI:0915”(physical association)	0.400
	SCO2	psi-mi:“MI:0915”(physical association)	0.400
ISG20L2	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
Setd3	PACSIN1	psi-mi:“MI:0914”(association)	0.350
Setd2	PACSIN1	psi-mi:“MI:0914”(association)	0.350
SUCO	RPL10	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PPAN	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
NPM1	RPS3A	psi-mi:“MI:0914”(association)	0.350
PSPC1	MCRIP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): ISG20L2 (Two-hybrid), ISG20L2 (Two-hybrid), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Proximity Label-MS), ISG20L2 (Affinity Capture-MS), ISG20L2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPN4, A2AKB4, A2APT9, A4Q9E8, A4Q9F6, A6NNM8, A6QQJ8, A8CVX7, B2GUW6, D2H8V8, O88866, O94761, P48778, Q14154, Q2YDK1, Q3TYG6, Q49AM3, Q4KLY6, Q4QQS0, Q4R747, Q5D1E7, Q5D1E8, Q5NC05, Q5RA67, Q5REE2, Q5SXM2, Q60953, Q6ZQM0, Q6ZUX3, Q6ZW76, Q75NR7, Q7TSG2, Q8BIY3, Q8BP86, Q8C7W7, Q8IX06, Q8N841, Q8R2S1, Q8VCU0, Q8WTP8

Diamond homologs: A1A5R7, A1Z7K9, A3KPE8, A3LRV8, A4RF51, A5DAD0, A5E1W0, B2GUW6, G0SAK8, O94375, O94443, P0C581, P0CQ08, P0CQ09, P0CQ44, P0CQ45, P48778, P53010, P53015, P53331, Q08237, Q09798, Q0CJU7, Q10124, Q2GSV2, Q2T9U5, Q2YDK1, Q3U1G5, Q4PER6, Q4R9F7, Q4WYA1, Q504Q3, Q54U94, Q5AL29, Q5APK0, Q5B367, Q5F450, Q5REE2, Q6AXU3, Q6C462

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 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
Downstream signal transduction	5	51.4×	2e-05
FCGR3A-mediated phagocytosis	5	25.3×	3e-04
Signaling by ALK fusions and activated point mutants	5	20.3×	6e-04
VEGFA-VEGFR2 Pathway	5	18.8×	7e-04
Major pathway of rRNA processing in the nucleolus and cytosol	6	10.0×	2e-03
PIP3 activates AKT signaling	5	9.0×	5e-03
Metabolism of RNA	6	6.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

406 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156724142:TGCTA:T	donor_loss	1.0000
1:156724143:GCTAC:G	donor_loss	1.0000
1:156724144:CTA:C	donor_loss	1.0000
1:156724145:TA:T	donor_loss	1.0000
1:156724146:AC:A	donor_loss	1.0000
1:156724346:GAT:G	acceptor_gain	1.0000
1:156724348:TCT:T	acceptor_loss	1.0000
1:156724349:C:CA	acceptor_loss	1.0000
1:156724349:C:CC	acceptor_gain	1.0000
1:156724350:T:C	acceptor_loss	1.0000
1:156724358:G:C	acceptor_gain	1.0000
1:156724171:T:TA	donor_gain	0.9900
1:156724344:AAGAT:A	acceptor_gain	0.9900
1:156724345:AGAT:A	acceptor_gain	0.9900
1:156724347:AT:A	acceptor_gain	0.9900
1:156724358:G:GC	acceptor_gain	0.9900
1:156724360:G:C	acceptor_gain	0.9900
1:156724360:G:GC	acceptor_gain	0.9900
1:156726902:TTAC:T	donor_loss	0.9900
1:156726904:A:AC	donor_gain	0.9900
1:156726905:C:CC	donor_gain	0.9900
1:156726905:C:CT	donor_loss	0.9900
1:156726905:CCTGG:C	donor_gain	0.9900
1:156723462:CCTG:C	acceptor_loss	0.9800
1:156723463:CTGA:C	acceptor_loss	0.9800
1:156723464:T:C	acceptor_loss	0.9800
1:156728582:GTGT:G	donor_gain	0.9700
1:156724347:ATCTG:A	acceptor_gain	0.9600
1:156728569:C:T	donor_gain	0.9600
1:156723458:CCAAC:C	acceptor_gain	0.9500

AlphaMissense

2315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156727047:G:C	S202R	0.999
1:156727047:G:T	S202R	0.999
1:156727049:T:G	S202R	0.999
1:156723423:C:G	A330P	0.998
1:156723430:A:C	D327E	0.998
1:156723430:A:T	D327E	0.998
1:156724296:T:G	D267A	0.998
1:156726976:C:G	R226P	0.998
1:156727050:A:C	C201W	0.998
1:156727052:A:G	C201R	0.998
1:156723431:T:G	D327A	0.997
1:156723432:C:G	D327H	0.997
1:156723445:A:C	H322Q	0.997
1:156723445:A:T	H322Q	0.997
1:156723447:G:C	H322D	0.997
1:156724254:C:G	R281P	0.997
1:156724255:G:T	R281S	0.997
1:156724295:G:C	D267E	0.997
1:156724295:G:T	D267E	0.997
1:156724296:T:A	D267V	0.997
1:156724296:T:C	D267G	0.997
1:156724309:C:G	A263P	0.997
1:156724314:C:T	G261E	0.997
1:156724320:A:T	V259E	0.997
1:156727042:A:T	V204D	0.997
1:156727057:G:T	A199D	0.997
1:156727096:A:G	M186T	0.997
1:156727099:T:A	E185V	0.997
1:156727104:G:C	D183E	0.997
1:156727104:G:T	D183E	0.997

dbSNP variants (sampled 300 via entrez): RS1000505087 (1:156722859 G>A), RS1001183087 (1:156729224 A>G), RS1001219091 (1:156722529 G>A), RS1001537087 (1:156729292 G>A,T), RS1001609278 (1:156729531 T>C), RS1002227599 (1:156721397 G>T), RS1002386765 (1:156728244 C>A,T), RS1002490381 (1:156723661 T>C), RS1002747236 (1:156728529 C>A,T), RS1003166022 (1:156726293 G>A), RS1003220980 (1:156730539 C>T), RS1003758370 (1:156725110 C>A), RS1003801619 (1:156729405 CTTTT>C,CTT,CTTT,CTTTTT,CTTTTTT,CTTTTTTTTTTT), RS1004132256 (1:156724826 C>T), RS1004193378 (1:156724801 G>A,C,T)

Disease associations

OMIM: gene MIM:611930 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004607_206	Plateletcrit	3.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects methylation, decreases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	2
Ethyl Methanesulfonate	decreases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, increases expression	2
dicrotophos	increases expression	1
daidzein	affects cotreatment, affects expression	1
triphenyl phosphate	affects expression	1
daidzin	affects cotreatment, affects expression	1
afimoxifene	increases expression, decreases reaction	1
cobaltous chloride	decreases expression	1
genistin	affects cotreatment, affects expression	1
glycitein	affects expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
glycitin	affects cotreatment, affects expression	1
Adenine	decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	decreases expression	1
Colchicine	decreases expression	1
Bucladesine	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estrogens	decreases reaction, increases expression	1
Etoposide	decreases expression	1
Formaldehyde	decreases expression	1
Hydroxyurea	decreases expression	1
Indomethacin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

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