DIS3

Summary

DIS3 (DIS3 exosome endoribonuclease and 3’-5’ exoribonuclease, HGNC:20604) is a protein-coding gene on chromosome 13q21.33, encoding Exosome complex exonuclease RRP44 (Q9Y2L1). Putative catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. It is a selective cancer dependency (DepMap: 85.4% of cell lines).

Enables 3’-5’-RNA exonuclease activity; endonuclease activity; and guanyl-nucleotide exchange factor activity. Involved in CUT catabolic process; RNA processing; and rRNA catabolic process. Located in cytosol and nucleoplasm. Part of nuclear exosome (RNase complex).

Source: NCBI Gene 22894 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 158 total — 1 pathogenic, 2 likely-pathogenic
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 85.4% of screened cell lines
• MANE Select transcript: NM_014953

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20604
Approved symbol	DIS3
Name	DIS3 exosome endoribonuclease and 3’-5’ exoribonuclease
Location	13q21.33
Locus type	gene with protein product
Status	Approved
Aliases	dis3p, RRP44, EXOSC11
Ensembl gene	ENSG00000083520
Ensembl biotype	protein_coding
OMIM	607533
Entrez	22894

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000377767, ENST00000377780, ENST00000475871, ENST00000490646, ENST00000545453, ENST00000929767, ENST00000958787

RefSeq mRNA: 4 — MANE Select: NM_014953 NM_001128226, NM_001322348, NM_001322349, NM_014953

CCDS: CCDS45057, CCDS81772, CCDS9447

Canonical transcript exons

ENST00000377767 — 21 exons

Exon	Start	End
ENSE00000923650	72771081	72771145
ENSE00000923651	72771795	72771896
ENSE00000923654	72773684	72773821
ENSE00000923655	72773946	72774059
ENSE00000923659	72777420	72777493
ENSE00001121366	72770904	72770988
ENSE00001250231	72775211	72775375
ENSE00001355717	72752169	72759878
ENSE00001364184	72775925	72776092
ENSE00001927466	72781605	72781900
ENSE00003485310	72761363	72761521
ENSE00003521334	72772159	72772275
ENSE00003529866	72768785	72768912
ENSE00003551898	72760529	72760651
ENSE00003559660	72772693	72772839
ENSE00003583930	72778187	72778380
ENSE00003630761	72765972	72766058
ENSE00003631749	72763451	72763607
ENSE00003632437	72761923	72762137
ENSE00003671608	72761646	72761814
ENSE00003680822	72780846	72781003

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 94.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.3833 / max 321.5489, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137582	30.0902	1821
137583	4.1108	1483
137581	0.1067	21
137584	0.0470	10
137585	0.0235	5
207058	0.0051	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	94.14	gold quality
calcaneal tendon	UBERON:0003701	93.87	gold quality
male germ cell	CL:0000015	91.29	gold quality
ventricular zone	UBERON:0003053	87.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.65	gold quality
cortical plate	UBERON:0005343	87.52	gold quality
stromal cell of endometrium	CL:0002255	86.66	gold quality
ganglionic eminence	UBERON:0004023	86.37	gold quality
adrenal tissue	UBERON:0018303	86.03	gold quality
rectum	UBERON:0001052	85.18	gold quality
islet of Langerhans	UBERON:0000006	84.99	gold quality
popliteal artery	UBERON:0002250	84.90	gold quality
tibial artery	UBERON:0007610	84.90	gold quality
right testis	UBERON:0004534	84.63	gold quality
cartilage tissue	UBERON:0002418	84.61	gold quality
gall bladder	UBERON:0002110	84.56	gold quality
testis	UBERON:0000473	84.45	gold quality
descending thoracic aorta	UBERON:0002345	84.43	gold quality
esophagus mucosa	UBERON:0002469	84.35	gold quality
lymph node	UBERON:0000029	84.28	gold quality
aorta	UBERON:0000947	84.27	gold quality
monocyte	CL:0000576	84.22	gold quality
left testis	UBERON:0004533	84.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.06	gold quality
left ovary	UBERON:0002119	84.02	gold quality
leukocyte	CL:0000738	83.92	gold quality
mononuclear cell	CL:0000842	83.90	gold quality
ectocervix	UBERON:0012249	83.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.62	gold quality
thoracic aorta	UBERON:0001515	83.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.38
E-MTAB-10137	no	466.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

156 targeting DIS3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-605-3P	99.88	69.22	1833

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 85.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 27)

• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. There appears to be no interaction between human dis3 and other exosome subunits, however. (PMID:12419256)
• Data show that hDIS3 and hDIS3L are active exonucleases, but only hDIS3 has retained endonucleolytic activity, and suggest that three different ribonucleases can serve as catalytic subunits for the exosome in human cells. (PMID:20531386)
• Multiple myeloma-associated hDIS3 mutations interfere with hDIS3 exonucleolytic activity. (PMID:24150935)
• Overexpression of DIS3 and LRCH1 associated with adenoma to carcinoma progression is linked to the colorectal cancer specific gain of 13q. (PMID:24478024)
• seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. (PMID:25521164)
• The study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation. (PMID:25925570)
• structure and function of DIS3 (PMID:26193331)
• Results from a study on gene variability markers in early-stage human embryos shows that DIS3 is a putative variability marker for the 3-day, 8-cell embryo stage, identified by mixture models as well as standard ANOVA. (PMID:26288249)
• Data indicate the pathological relevance of exosome component 11 protein (DIS3) mutations in plasma cell dyscrasias and suggest that DIS3 may represent a potential tumor suppressor gene in such disorders. (PMID:26305418)
• Authors have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay. (PMID:28172817)
• DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers. (PMID:29802118)
• The 3.8 A resolution cryo-EM structure of the core complex bound to a single-stranded RNA reveals that the RNA channel path is formed by two distinct features of the hDIS3 exoribonuclease: an open conformation and a domain organization more similar to bacterial RNase II than to yeast Rrp44. (PMID:30047866)
• Here, we investigated the interplay of exosome-associated 3’-5’ exonucleases DIS3 and RRP6 in rRNA processing and by-product elimination in human cells (PMID:30266864)
• 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 loss of DIS3 has the greatest impact, causing the substantial accumulation of thousands of transcripts within 60 min. (PMID:30840897)
• The germline variants in DIS3. (PMID:30967618)
• We further demonstrate that polyQ-expanded huntingtin delays Dis3 degradation during heat stress and thus hinders chaperone mRNA stabilization. Our findings not only reveal a post-transcriptional negative feedback loop for maintaining proteostasis, but also uncover a mechanism that contributes to the impaired heat stress response in Huntington’s disease (PMID:31428776)
• BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma. (PMID:31988198)
• DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome. (PMID:33951891)
• RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis. (PMID:34059908)
• MicroRNA-125a/b-5p promotes malignant behavior in multiple myeloma cells and xenograft tumor growth by targeting DIS3. (PMID:35394705)
• MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus. (PMID:35902094)
• Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism. (PMID:36215697)
• DIS3: The Enigmatic Gene in Multiple Myeloma. (PMID:36835493)
• DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis. (PMID:36869713)
• DIS3 depletion in multiple myeloma causes extensive perturbation in cell cycle progression and centrosome amplification. (PMID:37439377)
• Dis3p is identical to Rrp44p, which comprises the exosome involved in ribosomal RNA processing. Similar to S. cerevisiae Dis3p, human Dis3p enhanced RCC1-stimulated nucleotide release from Ran, in a dose-dependent manner, and bound to GTP- or GDP-Ran. (PMID:9562621)
• S. cerevisiae Dis3p is identical to Rrp44p, which comprises the exosome involved in ribosomal RNA processing, S. cerevisiae Dis3p was found to be localized in the nucleolus. (PMID:9562621)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dis3	ENSDARG00000060559
mus_musculus	Dis3	ENSMUSG00000033166
rattus_norvegicus	Dis3	ENSRNOG00000009125
drosophila_melanogaster	Dis3	FBGN0039183
caenorhabditis_elegans		WBGENE00001001

Paralogs (2): DIS3L2 (ENSG00000144535), DIS3L (ENSG00000166938)

Protein

Protein identifiers

Exosome complex exonuclease RRP44 — Q9Y2L1 (reviewed: Q9Y2L1)

Alternative names: Protein DIS3 homolog, Ribosomal RNA-processing protein 44

All UniProt accessions (3): Q9Y2L1, F2Z2C0, G3V1J5

UniProt curated annotations — full annotation on UniProt →

Function. Putative catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding ‘pervasive’ transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3’ untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. DIS3 has both 3’-5’ exonuclease and endonuclease activities.

Subunit / interactions. Component of the RNA exosome complex; within the complex interacts with EXOSC4, EXOSC7 and EXOSC9 of the exosome core complex (Exo-9). The catalytically inactive RNA exosome core complex (Exo-9) associates with the catalytic subunit EXOSC10/RRP6. Exo-9 may associate with DIS3 to form the nucleolar exosome complex, or DIS3L to form the cytoplasmic exosome complex. Exo-9 is formed by a hexameric base ring consisting of the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and a cap ring consisting of EXOSC1, EXOSC2 and EXOSC3; DIS3 associates with the base ring of Exo-9. The RNA exosome complex associates with cofactors C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4. Interacts with DHX34; the interaction is RNA-independent.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Nucleoplasm.

Tissue specificity. Widely expressed.

Miscellaneous. The association of DIS3 with the RNA exosome complex appears to be weak explaining its absence in some complex purifications.

Similarity. Belongs to the RNR ribonuclease family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2L1-1	1	yes
Q9Y2L1-2	2

RefSeq proteins (4): NP_001121698, NP_001309277, NP_001309278, NP_055768* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001900	RNase_II/R	Domain
IPR002716	PIN_dom	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR022966	RNase_II/R_CS	Conserved_site
IPR029060	PIN-like_dom_sf	Homologous_superfamily
IPR033770	RRP44_S1	Domain
IPR033771	Rrp44_CSD1	Domain
IPR041505	Dis3_CSD2	Domain
IPR050180	RNR_Ribonuclease	Family

Pfam: PF00773, PF13638, PF17215, PF17216, PF17849

UniProt features (84 total): strand 36, helix 24, turn 8, domain 4, modified residue 3, sequence variant 2, mutagenesis site 2, chain 1, splice variant 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6D6Q	ELECTRON MICROSCOPY	3.45
6D6R	ELECTRON MICROSCOPY	3.45
6H25	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2L1-F1	86.12	0.52

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): 1, 18, 215

Mutagenesis-validated functional residues (2):

Position	Phenotype
146	loss of endonuclease activity; when associated with n-487.
487	loss of exonuclease activity. loss of endonuclease activity; when associated with n-146.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9930044	Nuclear RNA decay
R-HSA-2262752	Cellular responses to stress
R-HSA-381042	PERK regulates gene expression
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-429914	Deadenylation-dependent mRNA decay
R-HSA-450531	Regulation of mRNA stability by proteins that bind AU-rich elements
R-HSA-72312	rRNA processing
R-HSA-8868773	rRNA processing in the nucleus and cytosol
R-HSA-8953854	Metabolism of RNA
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 176 (showing top): chr13q21, GOBP_RIBOSOME_BIOGENESIS, GOMF_ENDONUCLEASE_ACTIVITY, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_SURVEILLANCE, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_DEADENYLATION_DEPENDENT_DECAY

GO Biological Process (9): nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), rRNA catabolic process (GO:0016075), nuclear mRNA surveillance of mRNA 3’-end processing (GO:0071031), CUT catabolic process (GO:0071034), nuclear-transcribed mRNA catabolic process (GO:0000956), gene expression (GO:0010467)

GO Molecular Function (9): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), endonuclease activity (GO:0004519), guanyl-nucleotide exchange factor activity (GO:0005085), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), RNA nuclease activity (GO:0004540), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Metabolism of RNA	4
Regulation of mRNA stability by proteins that bind AU-rich elements	3
PERK regulates gene expression	1
Deadenylation-dependent mRNA decay	1
rRNA processing in the nucleus and cytosol	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Cellular responses to stress	1
rRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclease activity	3
nuclear lumen	3
rRNA metabolic process	2
RNA catabolic process	2
exosome (RNase complex)	2
cytoplasm	2
intracellular anatomical structure	2
nuclear-transcribed mRNA catabolic process	1
mRNA destabilization	1
RNA processing	1
ribosome biogenesis	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
nuclear mRNA surveillance	1
nuclear polyadenylation-dependent mRNA catabolic process	1
mRNA catabolic process	1
macromolecule biosynthetic process	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
catalytic activity, acting on a nucleic acid	1
hydrolase activity, acting on ester bonds	1
catalytic activity, acting on RNA	1
binding	1
catalytic activity	1
nucleus	1
nuclear protein-containing complex	1
exoribonuclease complex	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIS3	EXOSC10	Q01780	999
DIS3	EXOSC8	Q96B26	967
DIS3	EXOSC7	Q15024	935
DIS3	EXOSC9	Q06265	929
DIS3	MTREX	P42285	910
DIS3	EXOSC4	Q9NPD3	910
DIS3	EXOSC1	Q9Y3B2	905
DIS3	EXOSC3	Q9NQT5	899
DIS3	EXOSC5	Q9NQT4	889
DIS3	C1D	Q13901	864
DIS3	EXOSC6	Q5RKV6	823
DIS3	EXOSC2	Q13868	819
DIS3	TENT5C	Q5VWP2	791
DIS3	ZCCHC7	Q8N3Z6	764
DIS3	XRN1	Q8IZH2	761

IntAct

172 interactions, top by confidence:

A	B	Type	Score
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
EXOSC3	EXOSC10	psi-mi:“MI:0403”(colocalization)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
EXOSC3	DIS3	psi-mi:“MI:0915”(physical association)	0.740
DIS3	EXOSC10	psi-mi:“MI:0914”(association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
DCX	ZBTB5	psi-mi:“MI:0914”(association)	0.670
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
MUS81	ERCC4	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
DIS3	EXOSC2	psi-mi:“MI:0915”(physical association)	0.620
DIS3	EXOSC2	psi-mi:“MI:0914”(association)	0.620
PIMREG	MTA2	psi-mi:“MI:0914”(association)	0.600
SSBP3	LHX1	psi-mi:“MI:0914”(association)	0.570
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
MUS81	ERCC1	psi-mi:“MI:0914”(association)	0.530
NELFE	IGHMBP2	psi-mi:“MI:0914”(association)	0.530
DCX	DCLK1	psi-mi:“MI:0914”(association)	0.530
WDR43	WDR75	psi-mi:“MI:0914”(association)	0.530

BioGRID (239): DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Co-fractionation), DIS3 (Co-fractionation), DIS3 (Co-fractionation), EXOSC10 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC7 (Co-fractionation), EXOSC9 (Co-fractionation), GNAS (Co-fractionation)

ESM2 similar proteins: A0JN80, A2RV18, A2VE39, D2HRF1, D3ZG52, D3ZVK1, E1BMP7, G3GTP0, I0IUP3, O02697, P0DM58, P37202, P42338, P48736, P49717, P49917, Q08162, Q0P4R5, Q0V9Q6, Q0V9R3, Q0WPN0, Q17632, Q3EBC8, Q3V3E1, Q5F310, Q5R5N8, Q5R6L3, Q5R981, Q5U2P0, Q5U2Z5, Q5ZKG3, Q6GN11, Q6NQJ6, Q80VJ4, Q8BTF7, Q8BTI9, Q8C0L9, Q8C0S1, Q8CI75, Q8N1G2

Diamond homologs: A0JN80, A2RV18, O14040, O84402, P0DM58, P37202, Q08162, Q0P4R5, Q0WPN0, Q17632, Q5R5N8, Q5U2P0, Q6GN11, Q6NQJ6, Q8C0S1, Q8CI75, Q8TF46, Q9CSH3, Q9PK00, Q9SHL7, Q9Y2L1, Q9Z848, D0Z8E6, Q09568, Q0V9R3, Q9ZJX9, O32231, O67834, P21499, P30851, P40611, P44907, P47950, P54084, P56123, P57628, Q02146, Q8IYB7, Q8K917, Q9KNY1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 208 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
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	6	28.8×	1e-05
KSRP (KHSRP) binds and destabilizes mRNA	6	28.8×	1e-05
mRNA decay by 3’ to 5’ exoribonuclease	5	27.0×	1e-04
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	5	24.0×	2e-04
Nuclear RNA decay	10	23.4×	7e-09
ATF4 activates genes in response to endoplasmic reticulum stress	5	15.4×	2e-03
Major pathway of rRNA processing in the nucleolus and cytosol	13	6.1×	4e-05
mRNA Splicing - Major Pathway	11	4.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
maturation of 5.8S rRNA	5	28.2×	1e-04
RNA catabolic process	7	17.1×	6e-05
intrinsic apoptotic signaling pathway	6	11.5×	1e-03
RNA processing	9	10.5×	6e-05
rRNA processing	10	7.6×	1e-04
positive regulation of cell growth	7	6.9×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	121
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
150124	GRCh38/hg38 13q21.31-22.1(chr13:64065900-73693578)x3	Pathogenic
4759281	NM_014953.5(DIS3):c.1912C>T (p.Arg638Ter)	Likely pathogenic
800341	NM_014953.5(DIS3):c.2335A>T (p.Ile779Phe)	Likely pathogenic

SpliceAI

2765 predictions. Top by Δscore:

Variant	Effect	Δscore
13:72753684:T:TA	acceptor_gain	1.0000
13:72753687:CA:C	acceptor_loss	1.0000
13:72753688:A:AG	acceptor_gain	1.0000
13:72753688:AGAT:A	acceptor_gain	1.0000
13:72753688:AGATG:A	acceptor_gain	1.0000
13:72753689:G:GT	acceptor_gain	1.0000
13:72753689:GA:G	acceptor_gain	1.0000
13:72753689:GAT:G	acceptor_gain	1.0000
13:72753689:GATG:G	acceptor_gain	1.0000
13:72753689:GATGG:G	acceptor_gain	1.0000
13:72753820:AGG:A	donor_loss	1.0000
13:72753821:GGTAC:G	donor_loss	1.0000
13:72753822:G:A	donor_loss	1.0000
13:72753823:T:A	donor_loss	1.0000
13:72760523:CCTTA:C	donor_loss	1.0000
13:72760524:CTTAC:C	donor_loss	1.0000
13:72760525:TTACC:T	donor_loss	1.0000
13:72760526:TAC:T	donor_loss	1.0000
13:72760527:A:AC	donor_gain	1.0000
13:72760528:C:CC	donor_gain	1.0000
13:72760651:TC:T	acceptor_loss	1.0000
13:72760652:C:CC	acceptor_gain	1.0000
13:72760652:CTA:C	acceptor_loss	1.0000
13:72761518:ATAA:A	acceptor_gain	1.0000
13:72761519:TAA:T	acceptor_gain	1.0000
13:72761521:AC:A	acceptor_loss	1.0000
13:72761522:C:CC	acceptor_gain	1.0000
13:72761522:C:CG	acceptor_loss	1.0000
13:72761641:AATAC:A	donor_loss	1.0000
13:72761642:ATACC:A	donor_loss	1.0000

AlphaMissense

6351 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:72761923:C:G	R781T	1.000
13:72761926:C:G	R780T	1.000
13:72763565:A:C	N671K	1.000
13:72763565:A:T	N671K	1.000
13:72772202:T:A	D487V	1.000
13:72772838:C:T	G414E	1.000
13:72773710:A:G	W405R	1.000
13:72773710:A:T	W405R	1.000
13:72773724:A:T	V400D	1.000
13:72761666:A:G	S831P	0.999
13:72761669:C:G	A830P	0.999
13:72761671:C:G	R829P	0.999
13:72761677:G:T	A827D	0.999
13:72761687:C:G	A824P	0.999
13:72761698:C:G	R820P	0.999
13:72761703:A:C	N818K	0.999
13:72761703:A:T	N818K	0.999
13:72761791:C:G	R789P	0.999
13:72761795:G:C	H788D	0.999
13:72761807:C:G	D784H	0.999
13:72761814:T:A	R781S	0.999
13:72761814:T:G	R781S	0.999
13:72761923:C:A	R781I	0.999
13:72761925:T:A	R780S	0.999
13:72761925:T:G	R780S	0.999
13:72761932:G:T	P778H	0.999
13:72761940:A:C	F775L	0.999
13:72761940:A:T	F775L	0.999
13:72761942:A:G	F775L	0.999
13:72761945:G:C	H774D	0.999

dbSNP variants (sampled 300 via entrez): RS1000033807 (13:72768077 A>G), RS1000104366 (13:72751810 T>C), RS1000158630 (13:72754915 T>C,G), RS1000314667 (13:72778883 G>C), RS1000487398 (13:72767141 T>C), RS1000495450 (13:72756482 C>T), RS1000619768 (13:72762082 G>T), RS1000939267 (13:72755452 T>A,C), RS1001248030 (13:72773021 G>A,C), RS1001364153 (13:72773290 C>T), RS1001560818 (13:72761269 C>T), RS1001647882 (13:72779355 T>C,G), RS1001669510 (13:72773334 C>T), RS1001828683 (13:72754313 T>A,C), RS1001888161 (13:72762307 T>C)

Disease associations

OMIM: gene MIM:607533 | disease phenotypes: MIM:267000, MIM:254500

GenCC curated gene-disease

Mondo (2): Perlman syndrome (MONDO:0009965), plasma cell myeloma (MONDO:0009693)

Orphanet (3): Perlman syndrome (Orphanet:2849), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005042_13	Restless legs syndrome	3.000000e-09

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
C536399	Nephroblastomatosis, fetal ascites, macrosomia and Wilms tumor (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067309 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	affects expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	increases expression	1
Cannabidiol	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Mitoxantrone	affects response to substance	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	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
CHEMBL5651283	Binding	Binding affinity to human DIS3 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study
NCT05722405	PHASE4	RECRUITING	Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma
NCT05855122	PHASE4	UNKNOWN	Safety and ASCT-related Symptom Burden Optimization of Tocilizumab in ASCT Following HD Melphalan Conditioning for Multiple Myeloma Patients
NCT05944783	PHASE4	NOT_YET_RECRUITING	Bioequivalence Studies of Dasatinib 100 Mg
NCT06057402	PHASE4	RECRUITING	Elranatamab Post Trial Access Study for Participants With Multiple Myeloma (MM)
NCT06251076	PHASE4	RECRUITING	Plan Development for Giving Teclistamab in the Outpatient Setting