XRN2

Summary

XRN2 (5’-3’ exoribonuclease 2, HGNC:12836) is a protein-coding gene on chromosome 20p11.22, encoding 5’-3’ exoribonuclease 2 (Q9H0D6). Possesses 5’->3’ exoribonuclease activity. It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

This gene encodes a 5’-3’ exonuclease that promotes transcription termination at cotranscriptional cleavage sites. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 22803 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 139 total — 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_012255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12836
Approved symbol	XRN2
Name	5’-3’ exoribonuclease 2
Location	20p11.22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000088930
Ensembl biotype	protein_coding
OMIM	608851
Entrez	22803

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000377191, ENST00000903939, ENST00000903940, ENST00000903941, ENST00000915691, ENST00000915692, ENST00000915693, ENST00000915694, ENST00000915695, ENST00000915696, ENST00000948640, ENST00000948641, ENST00000948642, ENST00000948643

RefSeq mRNA: 2 — MANE Select: NM_012255 NM_001317960, NM_012255

CCDS: CCDS13144

Canonical transcript exons

ENST00000377191 — 30 exons

Exon	Start	End
ENSE00000564340	21328559	21328670
ENSE00000564370	21333937	21333994
ENSE00000564382	21340721	21340852
ENSE00000564389	21346415	21346550
ENSE00000564393	21348146	21348253
ENSE00000564397	21348341	21348430
ENSE00000564434	21354789	21354872
ENSE00000660857	21330481	21330539
ENSE00000660859	21330616	21330705
ENSE00000660861	21331561	21331633
ENSE00000660863	21331768	21331818
ENSE00000660865	21332283	21332440
ENSE00000660867	21333544	21333618
ENSE00000660869	21333704	21333837
ENSE00000660874	21334078	21334185
ENSE00000660875	21339044	21339088
ENSE00000660879	21344090	21344208
ENSE00000660887	21349389	21349461
ENSE00000660890	21356080	21356177
ENSE00000660891	21356586	21356665
ENSE00000660892	21357736	21357792
ENSE00000660893	21365421	21365489
ENSE00000660894	21365573	21365704
ENSE00000660895	21368463	21368590
ENSE00000660896	21381994	21382057
ENSE00000660897	21386868	21387006
ENSE00001131645	21389273	21389825
ENSE00001473202	21303331	21303473
ENSE00003468203	21326279	21326406
ENSE00003499254	21326490	21326601

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 96.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.8975 / max 997.1908, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183793	92.9429	1824
183792	2.7433	1516
183794	2.2113	1096

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.64	gold quality
leukocyte	CL:0000738	96.51	gold quality
ganglionic eminence	UBERON:0004023	95.57	gold quality
cortical plate	UBERON:0005343	95.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.21	gold quality
islet of Langerhans	UBERON:0000006	95.15	gold quality
smooth muscle tissue	UBERON:0001135	94.66	gold quality
calcaneal tendon	UBERON:0003701	94.65	gold quality
vermiform appendix	UBERON:0001154	94.19	gold quality
gall bladder	UBERON:0002110	93.80	gold quality
ventricular zone	UBERON:0003053	93.55	gold quality
stromal cell of endometrium	CL:0002255	93.38	gold quality
left adrenal gland	UBERON:0001234	92.99	gold quality
right adrenal gland	UBERON:0001233	92.93	gold quality
granulocyte	CL:0000094	92.92	gold quality
adrenal tissue	UBERON:0018303	92.85	gold quality
right adrenal gland cortex	UBERON:0035827	92.73	gold quality
body of pancreas	UBERON:0001150	92.60	gold quality
left adrenal gland cortex	UBERON:0035825	92.56	gold quality
pancreas	UBERON:0001264	92.55	gold quality
rectum	UBERON:0001052	92.46	gold quality
adrenal gland	UBERON:0002369	92.36	gold quality
left uterine tube	UBERON:0001303	92.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.13	gold quality
mucosa of stomach	UBERON:0001199	91.95	gold quality
body of uterus	UBERON:0009853	91.95	gold quality
right lung	UBERON:0002167	91.88	gold quality
tibial artery	UBERON:0007610	91.88	gold quality
popliteal artery	UBERON:0002250	91.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6524	no	520.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting XRN2, 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-450A-1-3P	100.00	69.33	1837
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-1277-5P	100.00	73.95	5056
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 29)

• co-transcriptional cleavage acts as a precursor to termination by presenting a free RNA 5’ end that is recognized by the human 5’ –> 3’ exonuclease Xrn2 (PMID:15565158)
• XRN2b is mainly expressed in blood leukocyte tissue, while XRN2a is detected in several human tissues and in human tumor tissues (PMID:16147866)
• p54 is present along the length of genes, and small interfering RNA (siRNA)-mediated knockdown leads to defects in XRN2 recruitment and termination. (PMID:17639083)
• Degradation of the downstream cleavage product (DCP) does not depend on the Xrn2 5’ exonuclease, suggesting that CPSF-73 degrades the DCP both in vitro and in vivo. (PMID:18955505)
• Genetic variants regulating Xrn2 expression in cis are determinants of spontaneous lung tumor susceptibility in mice and have genetic equivalents in lung cancer susceptibility in human beings. (PMID:19915612)
• The results predict that senataxin is required for the resolution of R-loops formed downstream of the poly(A) signal, allowing Xrn2 recruitment and efficient Pol II transcriptional termination. (PMID:21700224)
• Xrn2 has a role in control of transcription by RNA polymerase II. (PMID:22483619)
• Xrn2 associated with and co-transcriptionally degraded nascent beta-globin transcripts. Evidence was provided that many endogenous pre-mRNAs are also co-transcriptionally degraded by Xrn2 when their processing is inhibited by Spliceostatin A. (PMID:22522706)
• Microprocessor orchestrates the recruitment of termination factors Setx and Xrn2, and the 3’-5’ exoribonuclease, Rrp6, to initiate RNAPII pausing and premature termination at the HIV-1 promoter through cleavage of the stem-loop RNA, TAR. (PMID:22980978)
• hnRNPK may play a role in recruitment of XRN2 to gene loci thus regulating coupling 3’-end pre-mRNA processing to transcription termination. (PMID:23857582)
• Xrn2 has a cytoplasmic, antiviral function against HCV that is counteracted by HCV’s subversion of miR-122 to form a protective oligomeric complex at the 5’ end of the viral genome. (PMID:25121753)
• Mammalian target of rapamycin protein regulates the diffusion of Xrn2 from the nucleolus to the nucleoplasm under heat stress conditions. (PMID:25128458)
• The restriction of JFH1 and H77D hepatitis C virus replication by Xrn2 is likely indirect in nature and possibly linked to cytopathic effects of these robustly replicating viruses. (PMID:25673723)
• found that the 3’ fragments of target pre-mRNA generated by ASO were almost completely degraded from their 5’ ends by nuclear XRN2 after RNase H1-mediated cleavage (PMID:26159921)
• Chromatin immunoprecipitation experiments further show that IL-1 stimulation leads to decrease in NKRF aa 421-429 phosphorylation and dissociation of NELF-E and XRN2 by concomitant resumption of transcription elongation of a synthetic reporter (PMID:26340924)
• Kinetic competition between elongating pol II and the Xrn2 exonuclease is integral to termination of transcription on most human genes. (PMID:26474067)
• The results suggest that CARF regulates early steps of pre-rRNA processing during ribosome biogenesis by controlling spatial distribution of XRN2 between the nucleoplasm and nucleolus. (PMID:26531822)
• P-TEFb regulates termination by promoting chromatin recruitment and activation of a cotranscriptional RNA processing enzyme, Xrn2. (PMID:26728557)
• XRN2 has a role in R-loop resolution, suppression of replication stress, and maintenance of genomic stability (PMID:27437695)
• depletion of NKRF, XRN2 or DHX15 impairs an early pre-rRNA cleavage step. (PMID:28115624)
• XRN2 is a novel regulator of EMT that contributes to the metastatic processes in lung cancer through a novel miRNA regulatory mechanism. (PMID:28319071)
• Xrn2 depletion induces a transcriptional termination defect at the majority of protein-coding genes. (PMID:30035655)
• Authors engineered cells in which the 3’–>5’ exoribonucleases of the exosome complex, DIS3 and EXOSC10, can be rapidly eliminated to assess their immediate roles in nuclear RNA biology. The 5’–>3’ exoribonuclease, XRN2, has little activity on exosome substrates, but its elimination uncovers different mechanisms for the early termination of transcription from protein-coding gene promoters. (PMID:30840897)
• XRN2, a gene proximal to an autism spectrum disorder (ASD) genome-wide association study (GWAS) locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. (PMID:31230729)
• Genome-wide R-loop analysis defines unique roles for DDX5, XRN2, and PRMT5 in DNA/RNA hybrid resolution. (PMID:32747416)
• Upregulation of XRN2 acts as an oncogene in oral squamous cell carcinoma and correlates with poor prognosis. (PMID:33626405)
• XRN2 Is Required for Cell Motility and Invasion in Glioblastomas. (PMID:35563787)
• The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer. (PMID:36344846)
• The exoribonuclease XRN2 mediates degradation of the long non-coding telomeric RNA TERRA. (PMID:37191774)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	xrn2	ENSDARG00000101900
mus_musculus	Xrn2	ENSMUSG00000027433
rattus_norvegicus	Xrn2	ENSRNOG00000011785
drosophila_melanogaster	Rat1	FBGN0031868
caenorhabditis_elegans		WBGENE00006964

Paralogs (1): XRN1 (ENSG00000114127)

Protein

Protein identifiers

5’-3’ exoribonuclease 2 — Q9H0D6 (reviewed: Q9H0D6)

Alternative names: DHM1-like protein

All UniProt accessions (1): Q9H0D6

UniProt curated annotations — full annotation on UniProt →

Function. Possesses 5’->3’ exoribonuclease activity. May promote the termination of transcription by RNA polymerase II. During transcription termination, cleavage at the polyadenylation site liberates a 5’ fragment which is subsequently processed to form the mature mRNA and a 3’ fragment which remains attached to the elongating polymerase. The processive degradation of this 3’ fragment by this protein may promote termination of transcription. Binds to RNA polymerase II (RNAp II) transcription termination R-loops formed by G-rich pause sites.

Subunit / interactions. Interacts with POLR2A and SMN1/SMN2. Interacts with CDKN2AIP and NKRF. Interacts with CDKN2AIPNL; the interaction is direct. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner. Interacts with DHX34; the interaction is RNA-independent.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Expressed in the spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Isoform 2 is expressed predominantly in peripheral blood leukocytes.

Similarity. Belongs to the 5’-3’ exonuclease family. XRN2/RAT1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0D6-1	1, XRN2a	yes
Q9H0D6-2	2, XRN2b

RefSeq proteins (2): NP_001304889, NP_036387* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004859	Xrn1_N	Domain
IPR017151	Xrn2/3/4	Family
IPR027073	5_3_exoribonuclease	Family
IPR041412	Xrn1_helical	Domain

Pfam: PF03159, PF17846

Enzyme classification (BRENDA):

• EC 3.1.13.1 — exoribonuclease II (BRENDA: 33 organisms, 123 substrates, 47 inhibitors, 4 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
POLY(A)	0.0003–0.0013	2
POLY(U)	0.0001	1
POLYADENOSINE	0.0004	1

UniProt features (48 total): modified residue 23, sequence conflict 14, compositionally biased region 4, region of interest 2, sequence variant 2, chain 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0D6-F1	78.15	0.54

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 (23): 448, 471, 473, 475, 482, 487, 499, 501, 678, 824, 824, 847, 847, 851, 851, 880, 883, 883, 895, 946 …

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 187 (showing top): GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, MODULE_255, GOMF_NUCLEASE_ACTIVITY, SP3_Q3, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_NEUROGENESIS, GOBP_MALE_GAMETE_GENERATION, USF_C, GOBP_FOREBRAIN_DEVELOPMENT, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (13): nuclear-transcribed mRNA catabolic process (GO:0000956), rRNA processing (GO:0006364), termination of RNA polymerase II transcription (GO:0006369), RNA processing (GO:0006396), mRNA processing (GO:0006397), RNA catabolic process (GO:0006401), spermatogenesis (GO:0007283), RNA metabolic process (GO:0016070), hippocampus development (GO:0021766), neuron differentiation (GO:0030182), retina development in camera-type eye (GO:0060041), nucleobase-containing compound metabolic process (GO:0006139), DNA-templated transcription termination (GO:0006353)

GO Molecular Function (14): transcription termination site sequence-specific DNA binding (GO:0001147), RNA binding (GO:0003723), nuclease activity (GO:0004518), 5’-3’ RNA exonuclease activity (GO:0004534), zinc ion binding (GO:0008270), 5’-3’ exonuclease activity (GO:0008409), identical protein binding (GO:0042802), 3’-5’-RNA exonuclease activity (GO:0000175), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), membrane (GO:0016020), aggresome (GO:0016235)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
rRNA processing in the nucleus and cytosol	1
mRNA 3’-end processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
DNA-templated transcription termination	2
RNA biosynthetic process	2
primary metabolic process	2
anatomical structure development	2
nucleic acid binding	2
RNA exonuclease activity, producing 5’-phosphomonoesters	2
binding	2
nuclear lumen	2
cellular anatomical structure	2
mRNA catabolic process	1
rRNA metabolic process	1
ribosome biogenesis	1
transcription by RNA polymerase II	1
gene expression	1
mRNA metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
nucleic acid metabolic process	1
pallium development	1
limbic system development	1
cell differentiation	1
generation of neurons	1
camera-type eye development	1
DNA-templated transcription	1
transcription cis-regulatory region binding	1
catalytic activity, acting on a nucleic acid	1
5’-3’ exonuclease activity	1
transition metal ion binding	1
exonuclease activity	1
protein binding	1
3’-5’ exonuclease activity	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XRN2	DXO	O77932	951
XRN2	ERI2	A8K979	946
XRN2	DCP2	Q8IU60	899
XRN2	DNASE1L2	Q92874	854
XRN2	SETX	Q7Z333	843
XRN2	SKIC2	Q15477	774
XRN2	EXOSC10	Q01780	762
XRN2	DICER1	Q9UPY3	756
XRN2	UPF1	Q92900	737
XRN2	TJAP1	Q5JTD0	736
XRN2	CPSF3	Q9UKF6	717
XRN2	DCP1A	Q9NPI6	707
XRN2	DIS3	Q9Y2L1	688
XRN2	UPF2	Q9HAU5	666
XRN2	TUT1	Q9H6E5	653

IntAct

182 interactions, top by confidence:

A	B	Type	Score
CDKN2AIPNL	XRN2	psi-mi:“MI:0915”(physical association)	0.800
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
XRN2	CDKN2AIP	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TARDBP	XRN2	psi-mi:“MI:0915”(physical association)	0.670
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
SMN1	PRMT5	psi-mi:“MI:0914”(association)	0.600
POLR2A	PRMT5	psi-mi:“MI:0914”(association)	0.560
TTC23	XRN2	psi-mi:“MI:0915”(physical association)	0.560
LCN2	XRN2	psi-mi:“MI:0915”(physical association)	0.560
XRN2	XRN2	psi-mi:“MI:0915”(physical association)	0.560
CRY2	XRN2	psi-mi:“MI:0915”(physical association)	0.560
XRN2	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
CDKN2AIP	MAGEB2	psi-mi:“MI:0914”(association)	0.530
CDKN2AIP	PCF11	psi-mi:“MI:0914”(association)	0.530
CDKN2AIPNL	KPNA1	psi-mi:“MI:0914”(association)	0.530
DCAF7	CLASP2	psi-mi:“MI:0914”(association)	0.510
DHX58	NKRF	psi-mi:“MI:0914”(association)	0.500
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
DDX21	XRN2	psi-mi:“MI:0915”(physical association)	0.400
CPLANE1	XRN2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (493): XRN2 (Affinity Capture-RNA), XRN2 (Affinity Capture-RNA), XRN2 (Affinity Capture-RNA), XRN2 (Affinity Capture-RNA), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS), CFAP58 (Co-fractionation), MCFD2 (Co-fractionation), XRN2 (Co-fractionation), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS), XRN2 (Affinity Capture-MS)

ESM2 similar proteins: A3KN83, A8XYX2, F4IF36, O01991, O18017, O82486, P0CO28, P0CO29, P13382, P40848, P43125, P97496, Q02792, Q07422, Q0IQN5, Q10988, Q24168, Q2GNZ6, Q2HVD6, Q2UCP5, Q4HWE2, Q4P149, Q4P3S3, Q4WQJ1, Q5BFH3, Q5F371, Q5R4L5, Q5ZIP4, Q689Z5, Q68FR9, Q6EU10, Q6NZC7, Q6P158, Q74ZA0, Q7Z478, Q8TFZ1, Q8WZX5, Q92922, Q93YQ1, Q9DBR1

Diamond homologs: P0CL88, P0CL89, P40383, P40848, P97789, Q02792, Q2GNZ6, Q2UCP5, Q4HWE2, Q4P149, Q5AMG5, Q5BFH3, Q5R4L5, Q5ZIP4, Q60SG7, Q6BNU7, Q6C961, Q6CKX0, Q6FKN6, Q74ZA0, Q8IZH2, Q8TFZ1, Q8WZX5, Q9DBR1, Q9FQ02, Q9FQ03, Q9FQ04, Q9H0D6, Q9U299, Q9VM71, P22147, Q197A1, Q5UQ94, P23252

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CDK7	“up-regulates activity”	XRN2	phosphorylation
RNF8	“up-regulates activity”	XRN2	ubiquitination
CDK9	“up-regulates activity”	XRN2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 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
Processing of Capped Intron-Containing Pre-mRNA	18	12.3×	3e-12
mRNA Polyadenylation	16	11.7×	1e-10
mRNA 3’-end processing	7	11.5×	2e-04
mRNA Splicing - Minor Pathway	6	11.2×	1e-03
mRNA Splicing	11	10.1×	2e-06
mRNA Splicing - Major Pathway	19	8.7×	1e-10
Dengue Virus-Host Interactions	18	6.8×	2e-08
Metabolism of RNA	15	5.2×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal complex assembly	6	23.0×	5e-05
translational initiation	5	11.4×	6e-03
autophagosome maturation	5	11.2×	6e-03
regulation of alternative mRNA splicing, via spliceosome	7	10.9×	6e-04
mRNA splicing, via spliceosome	16	9.3×	2e-08
negative regulation of translation	7	8.7×	2e-03
RNA splicing	15	8.4×	2e-07
mRNA processing	15	7.5×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	87
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3068499	Single allele	Likely pathogenic

SpliceAI

4414 predictions. Top by Δscore:

Variant	Effect	Δscore
20:21303470:GAAG:G	donor_gain	1.0000
20:21303471:AAGG:A	donor_loss	1.0000
20:21303474:GT:G	donor_loss	1.0000
20:21326407:G:GG	donor_gain	1.0000
20:21328652:G:T	donor_gain	1.0000
20:21330476:TCTA:T	acceptor_loss	1.0000
20:21330478:TAGGT:T	acceptor_loss	1.0000
20:21330479:A:C	acceptor_loss	1.0000
20:21330480:G:A	acceptor_loss	1.0000
20:21330535:CACCA:C	donor_gain	1.0000
20:21330536:ACCA:A	donor_gain	1.0000
20:21330537:CCA:C	donor_gain	1.0000
20:21330537:CCAGT:C	donor_loss	1.0000
20:21330538:CA:C	donor_gain	1.0000
20:21330538:CAG:C	donor_loss	1.0000
20:21330539:AG:A	donor_loss	1.0000
20:21330540:G:GG	donor_gain	1.0000
20:21330540:GTA:G	donor_loss	1.0000
20:21330541:TAAGT:T	donor_loss	1.0000
20:21330542:A:AG	donor_loss	1.0000
20:21330543:AGTAG:A	donor_loss	1.0000
20:21330610:TTTTA:T	acceptor_loss	1.0000
20:21330611:TTTAG:T	acceptor_loss	1.0000
20:21330612:TTAGG:T	acceptor_loss	1.0000
20:21330613:TA:T	acceptor_loss	1.0000
20:21330614:A:AC	acceptor_loss	1.0000
20:21330614:A:AG	acceptor_gain	1.0000
20:21330614:AG:A	acceptor_gain	1.0000
20:21330614:AGG:A	acceptor_gain	1.0000
20:21330615:G:GG	acceptor_gain	1.0000

AlphaMissense

6322 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:21303402:G:A	G2R	1.000
20:21303402:G:C	G2R	1.000
20:21303403:G:A	G2E	1.000
20:21303409:C:A	P4Q	1.000
20:21303417:T:C	F7L	1.000
20:21303419:C:A	F7L	1.000
20:21303419:C:G	F7L	1.000
20:21303420:C:A	R8S	1.000
20:21303423:T:A	W9R	1.000
20:21303423:T:C	W9R	1.000
20:21303427:T:C	L10P	1.000
20:21326355:T:C	L51P	1.000
20:21326361:T:C	L53S	1.000
20:21326363:G:C	D54H	1.000
20:21326364:A:C	D54A	1.000
20:21326364:A:T	D54V	1.000
20:21326365:T:A	D54E	1.000
20:21326365:T:G	D54E	1.000
20:21326369:A:C	N56H	1.000
20:21326369:A:G	N56D	1.000
20:21326370:A:T	N56I	1.000
20:21326371:T:A	N56K	1.000
20:21326371:T:G	N56K	1.000
20:21326372:G:A	G57R	1.000
20:21326372:G:C	G57R	1.000
20:21326373:G:A	G57E	1.000
20:21326379:T:A	I59N	1.000
20:21326381:C:G	H60D	1.000
20:21326383:T:A	H60Q	1.000
20:21326383:T:G	H60Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000100413 (20:21382621 C>G,T), RS1000113184 (20:21319648 C>A,T), RS1000148428 (20:21373259 C>T), RS1000267448 (20:21363501 C>T), RS1000299311 (20:21337697 A>G), RS1000314514 (20:21355902 G>A), RS1000351418 (20:21376449 T>C), RS1000377456 (20:21389489 C>G,T), RS1000400422 (20:21389414 G>A), RS1000438615 (20:21319424 A>C,G), RS1000442878 (20:21350552 A>G), RS1000494956 (20:21320960 C>T), RS1000508200 (20:21364606 A>G), RS1000574098 (20:21363129 A>G), RS1000640093 (20:21314957 C>T)

Disease associations

OMIM: gene MIM:608851 | disease phenotypes: MIM:256450

GenCC curated gene-disease

Mondo (1): hyperinsulinemic hypoglycemia, familial, 1 (MONDO:0009734)

Orphanet (2): Autosomal dominant hyperinsulinism due to SUR1 deficiency (Orphanet:276575), Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency (Orphanet:276598)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002479_15	Lupus nephritis in systemic lupus erythematosus	5.000000e-06
GCST004630_70	Mean corpuscular hemoglobin	2.000000e-09
GCST007556_21	Autism spectrum disorder	3.000000e-07
GCST012227_1364	Hip circumference adjusted for BMI	2.000000e-09
GCST90002390_692	Mean corpuscular hemoglobin	3.000000e-21
GCST90002392_98	Mean corpuscular volume	9.000000e-19
GCST90002404_547	Red cell distribution width	7.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0008039	BMI-adjusted hip circumference
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066360 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.94	Kd	11.39	nM	CHEMBL5653589
7.94	ED50	11.39	nM	CHEMBL5653589
6.26	Kd	547.1	nM	CHEMBL3752910
6.26	ED50	547.1	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 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	2149793: Binding affinity to human XRN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0114	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149793: Binding affinity to human XRN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5471	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
sodium arsenite	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
tetrabromobisphenol A	increases expression	1
nickel sulfate	decreases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
deguelin	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	affects phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652835	Binding	Binding affinity to human XRN2 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

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7Y7	SEES3-1V human XRN2, clone1	Embryonic stem cell	Male
CVCL_A7Y8	SEES3-1V human XRN2, clone2	Embryonic stem cell	Male
CVCL_A7Y9	SEES3-1V human XRN2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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