RPUSD3

Summary

RPUSD3 (RNA pseudouridine synthase D3, HGNC:28437) is a protein-coding gene on chromosome 3p25.3, encoding Mitochondrial mRNA pseudouridine synthase RPUSD3 (Q6P087). Catalyzes uridine to pseudouridine isomerization (pseudouridylation) of specific mitochondrial mRNAs (mt-mRNAs), a post-transcriptional modification necessary for their translation. It is a selective cancer dependency (DepMap: 20.0% of cell lines).

This gene encodes a protein that functions in the assembly of the mitochondrial ribosome by adding a pseudouridine group to 16S rRNA. Loss of this gene results in causes defects in mitochondrial protein production. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 285367 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 73 total — 2 likely-pathogenic
• Cancer dependency (DepMap): dependent in 20.0% of screened cell lines
• MANE Select transcript: NM_173659

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28437
Approved symbol	RPUSD3
Name	RNA pseudouridine synthase D3
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC29784
Ensembl gene	ENSG00000156990
Ensembl biotype	protein_coding
OMIM	617759
Entrez	285367

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000383820, ENST00000418713, ENST00000423108, ENST00000424438, ENST00000427174, ENST00000433535, ENST00000433555, ENST00000433972, ENST00000451405, ENST00000460909, ENST00000464783, ENST00000466141, ENST00000472381, ENST00000473522, ENST00000475470, ENST00000484134, ENST00000485705, ENST00000870303, ENST00000870304, ENST00000923701, ENST00000923702, ENST00000923703, ENST00000923704, ENST00000923705, ENST00000923706, ENST00000954644, ENST00000954645

RefSeq mRNA: 5 — MANE Select: NM_173659 NM_001142547, NM_001351736, NM_001351737, NM_001351738, NM_173659

CCDS: CCDS2586, CCDS46744, CCDS87038

Canonical transcript exons

ENST00000383820 — 9 exons

Exon	Start	End
ENSE00001011217	9840532	9840616
ENSE00001164782	9840184	9840307
ENSE00001728810	9843890	9844008
ENSE00003554380	9839032	9839171
ENSE00003620238	9842199	9842243
ENSE00003658029	9837849	9838207
ENSE00003665048	9840698	9840805
ENSE00003667748	9841983	9842082
ENSE00003676581	9843465	9843601

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 95.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9662 / max 237.3654, expressed in 1811 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40985	25.9662	1811

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	95.32	gold quality
apex of heart	UBERON:0002098	94.80	gold quality
gastrocnemius	UBERON:0001388	94.36	gold quality
left testis	UBERON:0004533	94.04	gold quality
muscle of leg	UBERON:0001383	93.81	gold quality
right testis	UBERON:0004534	93.60	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.55	gold quality
granulocyte	CL:0000094	93.04	gold quality
ventral tegmental area	UBERON:0002691	92.95	gold quality
cerebellar vermis	UBERON:0004720	92.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.28	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.24	gold quality
right adrenal gland	UBERON:0001233	92.05	gold quality
testis	UBERON:0000473	92.02	gold quality
right adrenal gland cortex	UBERON:0035827	91.89	gold quality
heart left ventricle	UBERON:0002084	91.86	gold quality
right frontal lobe	UBERON:0002810	91.82	gold quality
prefrontal cortex	UBERON:0000451	91.76	gold quality
superior vestibular nucleus	UBERON:0007227	91.69	gold quality
cardiac ventricle	UBERON:0002082	91.57	gold quality
anterior cingulate cortex	UBERON:0009835	91.39	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.35	gold quality
lower esophagus mucosa	UBERON:0035834	91.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.32	gold quality
subthalamic nucleus	UBERON:0001906	91.18	gold quality
mucosa of transverse colon	UBERON:0004991	91.11	gold quality
medulla oblongata	UBERON:0001896	91.04	gold quality
cerebellar cortex	UBERON:0002129	91.04	gold quality
cerebellar hemisphere	UBERON:0002245	91.02	gold quality
right atrium auricular region	UBERON:0006631	91.02	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting RPUSD3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-198	98.70	67.32	920
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-6735-3P	96.10	63.81	600

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 20.0% of screened cell lines.

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rpusd3	ENSMUSG00000051169
rattus_norvegicus	Rpusd3	ENSRNOG00000009084
caenorhabditis_elegans		WBGENE00013967

Paralogs (3): RPUSD1 (ENSG00000007376), RPUSD4 (ENSG00000165526), RPUSD2 (ENSG00000166133)

Protein

Protein identifiers

Mitochondrial mRNA pseudouridine synthase RPUSD3 — Q6P087 (reviewed: Q6P087)

Alternative names: RNA pseudouridylate synthase domain-containing protein 3

All UniProt accessions (7): Q6P087, C9JM75, H7C0K7, H7C0R9, H7C1H7, H7C2C3, H7C454

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes uridine to pseudouridine isomerization (pseudouridylation) of specific mitochondrial mRNAs (mt-mRNAs), a post-transcriptional modification necessary for their translation. Acts at position 390 in COXI mt-mRNA and at position 697-699 in mitochondrial COXIII mt-mRNA. As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mitochondrial ribosomal RNA (16S mt-rRNA), controls 16S mt-rRNA abundance and may play a role in mitochondrial ribosome biogenesis.

Subunit / interactions. Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the pseudouridine synthase RluA family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q6P087-1	1	yes
Q6P087-2	2
Q6P087-3	3
Q6P087-4	4
Q6P087-5	5
Q6P087-6	6

RefSeq proteins (5): NP_001136019, NP_001338665, NP_001338666, NP_001338667, NP_775930* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006145	PsdUridine_synth_RsuA/RluA	Domain
IPR020103	PsdUridine_synth_cat_dom_sf	Homologous_superfamily
IPR050188	RluA_PseudoU_synthase	Family

Pfam: PF00849

Catalyzed reactions (Rhea), 1 shown:

• a uridine in mRNA = a pseudouridine in mRNA (RHEA:56644)

UniProt features (10 total): splice variant 3, sequence variant 3, transit peptide 1, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P087-F1	83.19	0.70

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 (1): 71

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6793080	rRNA modification in the mitochondrion
R-HSA-9937008	Mitochondrial mRNA modification

MSigDB gene sets: 83 (showing top): GOBP_RIBOSOME_BIOGENESIS, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_MRNA_MODIFICATION, GOBP_PSEUDOURIDINE_SYNTHESIS, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_RRNA_MODIFICATION, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, REACTOME_METABOLISM_OF_RNA, GOBP_POSITIVE_REGULATION_OF_TRANSLATION, GOBP_REGULATION_OF_TRANSLATION, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (6): mRNA processing (GO:0006397), mRNA modification (GO:0016556), positive regulation of mitochondrial translation (GO:0070131), mRNA pseudouridine synthesis (GO:1990481), pseudouridine synthesis (GO:0001522), RNA modification (GO:0009451)

GO Molecular Function (4): RNA binding (GO:0003723), pseudouridine synthase activity (GO:0009982), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), ribonucleoprotein granule (GO:0035770)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
rRNA processing in the mitochondrion	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA metabolic process	2
RNA modification	2
RNA processing	1
mitochondrial translation	1
positive regulation of translation	1
regulation of mitochondrial translation	1
pseudouridine synthesis	1
mRNA modification	1
RNA metabolic process	1
macromolecule modification	1
nucleic acid binding	1
intramolecular transferase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
intracellular membraneless organelle	1
supramolecular complex	1

Protein interactions and networks

STRING

2019 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPUSD3	NGRN	Q9NPE2	846
RPUSD3	TRUB2	O95900	842
RPUSD3	FASTKD2	Q9NYY8	830
RPUSD3	RPUSD1	Q9UJJ7	795
RPUSD3	PUS7L	Q9H0K6	763
RPUSD3	PUS1	Q9Y606	744
RPUSD3	PUS3	Q9BZE2	735
RPUSD3	RCC1L	Q96I51	735
RPUSD3	PTCD1	O75127	728
RPUSD3	PUSL1	Q8N0Z8	727
RPUSD3	TRUB1	Q8WWH5	724
RPUSD3	PUS7	Q96PZ0	721
RPUSD3	PUS10	Q3MIT2	716
RPUSD3	RPUSD2	Q8IZ73	715
RPUSD3	DDX28	Q9NUL7	639

IntAct

88 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
FAM120A	SYNCRIP	psi-mi:“MI:0914”(association)	0.640
RPUSD3	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
RPUSD3	KRT31	psi-mi:“MI:0915”(physical association)	0.560
RPUSD3		psi-mi:“MI:0915”(physical association)	0.560
KRT31	RPUSD3	psi-mi:“MI:0915”(physical association)	0.560
	RPUSD3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-1	RPUSD3	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	RPUSD3	psi-mi:“MI:0915”(physical association)	0.560
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
MINDY3	UBB	psi-mi:“MI:0914”(association)	0.530
MRPL13	GTPBP10	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
CHCHD4	ENSA	psi-mi:“MI:0914”(association)	0.530
RPUSD3	HSPD1	psi-mi:“MI:0914”(association)	0.530
PRR3	MRPS14	psi-mi:“MI:0914”(association)	0.530
LIN28B	ELAVL2	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530

BioGRID (223): RPUSD3 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-3 (Two-hybrid), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Biochemical Activity), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS), RPUSD3 (Affinity Capture-MS)

ESM2 similar proteins: A2RT67, A2RUS2, A3BN26, A4PCD4, A5PKL6, E9PYK3, F1ND48, O75616, P04053, P06526, P09838, P36195, P42118, Q08C69, Q0DST9, Q149F1, Q14AI6, Q17QT4, Q28C59, Q2TBK7, Q3U269, Q3U3W5, Q49MI3, Q4QQT0, Q4R6Y8, Q5E9Z1, Q5EBA0, Q5M721, Q5M934, Q5RL51, Q61846, Q66KI9, Q6DBR0, Q6P087, Q8BGG7, Q8IZ73, Q8NEC7, Q8TF42, Q8VCZ8, Q92089

Diamond homologs: Q14AI6, Q28C59, Q2TBK7, Q4QQT0, Q5E9Z1, Q6DBR0, Q6P087, Q96CM3, Q9CWX4, O66114, P0AA41, P0AA42, P47451, P50513, P53294, P59831, P65836, P65837, P74346, Q08C69, Q09709, Q0J4D4, Q12069, Q12362, Q1RJX7, Q3ECD0, Q45826, Q4UKQ3, Q5XET6, Q82WZ5, Q87MD4, Q87S65, Q8DBG5, Q8DEV0, Q8FEF9, Q8I3Z1, Q8P682, Q8VCZ8, Q8X6T6, Q8XYX8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 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
Mitochondrial ribosome-associated quality control	12	22.7×	6e-11
Mitochondrial translation initiation	10	19.5×	1e-08
Mitochondrial translation elongation	10	19.5×	1e-08
Mitochondrial translation	9	19.1×	8e-08
Mitochondrial translation termination	10	16.9×	4e-08
Transport of Mature mRNA derived from an Intron-Containing Transcript	6	14.1×	3e-04
Translation	10	9.6×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	10	21.2×	2e-08
mRNA transport	5	16.1×	4e-03
negative regulation of translation	5	11.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	50
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
225005	NM_173659.5(RPUSD3):c.724C>T (p.His242Tyr)	Likely pathogenic
225035	NM_173659.5(RPUSD3):c.646C>T (p.Arg216Cys)	Likely pathogenic

SpliceAI

1114 predictions. Top by Δscore:

Variant	Effect	Δscore
3:9840304:CTGT:C	acceptor_gain	1.0000
3:9840308:C:CC	acceptor_gain	1.0000
3:9840318:A:T	acceptor_gain	1.0000
3:9840321:C:CT	acceptor_gain	1.0000
3:9840530:A:AC	donor_gain	1.0000
3:9840531:C:CC	donor_gain	1.0000
3:9840612:CAGCA:C	acceptor_gain	1.0000
3:9840614:GCA:G	acceptor_gain	1.0000
3:9840615:CA:C	acceptor_gain	1.0000
3:9840615:CAC:C	acceptor_gain	1.0000
3:9840617:C:CC	acceptor_gain	1.0000
3:9840692:TCTCA:T	donor_loss	1.0000
3:9840693:CTCA:C	donor_loss	1.0000
3:9840695:CACC:C	donor_loss	1.0000
3:9840696:A:C	donor_loss	1.0000
3:9840804:CT:C	acceptor_gain	1.0000
3:9840806:C:CC	acceptor_gain	1.0000
3:9841981:A:AC	donor_gain	1.0000
3:9841981:ACTT:A	donor_gain	1.0000
3:9841982:C:CC	donor_gain	1.0000
3:9841982:CTTC:C	donor_gain	1.0000
3:9842083:C:CC	acceptor_gain	1.0000
3:9843884:A:AC	donor_gain	1.0000
3:9843884:AAT:A	donor_gain	1.0000
3:9839029:TA:T	donor_loss	0.9900
3:9839030:A:AC	donor_loss	0.9900
3:9839031:C:CC	donor_loss	0.9900
3:9839031:CCTGT:C	donor_gain	0.9900
3:9839170:CA:C	acceptor_gain	0.9900
3:9839172:C:CC	acceptor_gain	0.9900

AlphaMissense

2211 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:9840245:A:C	S221R	0.993
3:9840245:A:T	S221R	0.993
3:9840247:T:G	S221R	0.993
3:9840204:A:T	V235D	0.977
3:9838135:G:C	H313D	0.976
3:9840614:G:T	A173D	0.974
3:9839117:C:A	G260V	0.972
3:9840611:A:T	V174D	0.970
3:9839167:G:C	F243L	0.968
3:9839167:G:T	F243L	0.968
3:9839169:A:G	F243L	0.968
3:9842221:C:A	K95N	0.968
3:9842221:C:G	K95N	0.968
3:9840239:A:C	F223L	0.966
3:9840239:A:T	F223L	0.966
3:9840241:A:G	F223L	0.966
3:9840794:C:T	G140E	0.965
3:9840198:A:G	L237P	0.963
3:9838137:A:G	L312P	0.962
3:9840563:A:G	L190P	0.959
3:9840795:C:A	G140W	0.958
3:9838141:G:C	H311D	0.956
3:9841998:A:T	V131D	0.956
3:9838122:A:G	L317P	0.952
3:9839117:C:T	G260E	0.952
3:9840785:A:T	L143H	0.950
3:9839118:C:A	G260W	0.949
3:9838055:G:C	F339L	0.947
3:9838055:G:T	F339L	0.947
3:9838057:A:G	F339L	0.947

dbSNP variants (sampled 300 via entrez): RS1000941594 (3:9841108 C>G), RS1001033478 (3:9839984 G>A,T), RS1001089270 (3:9845384 C>G,T), RS1001769068 (3:9838965 G>C,T), RS1001881729 (3:9841630 G>A), RS1002076489 (3:9845886 C>T), RS1003035938 (3:9837537 T>C), RS1003265695 (3:9844044 A>C,G), RS1003524909 (3:9842897 T>A), RS1003744292 (3:9842640 G>C), RS1003881331 (3:9840276 TC>T), RS1004293069 (3:9844935 A>C), RS1005164261 (3:9840331 C>A,G,T), RS1005496751 (3:9839399 AC>A), RS1005512176 (3:9844665 C>G)

Disease associations

OMIM: gene MIM:617759 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
Cisplatin	increases expression, affects expression, affects cotreatment	2
biochanin A	decreases expression	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Decitabine	affects expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Copper	decreases expression, affects binding	1
Doxorubicin	affects expression	1
Hydrogen Peroxide	affects expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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