Details for: PUS1

Gene ID: 80324

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PUS1

Ensembl ID: ENSG00000177192

Description: pseudouridine synthase 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • common myeloid progenitor CL0000049
    CSI 3.22
    rCSI 2.6%
    PRS 97.1
  • plasmacytoid dendritic cell, human CL0001058
    CSI 2.99
    rCSI 2.09%
    PRS 97.7
  • keratinocyte CL0000312
    CSI 2.92
    rCSI 2.45%
    PRS 95.66
  • hepatocyte CL0000182
    CSI 2.85
    rCSI 5.1%
    PRS 94.59
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.63
    rCSI 2.37%
    PRS 95.82
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.52
    rCSI 2.18%
    PRS 97.17
  • promyelocyte CL0000836
    CSI 2.43
    rCSI 3.51%
    PRS 96.87
  • club cell CL0000158
    CSI 2.06
    rCSI 3.02%
    PRS 94.08
  • transit amplifying cell of colon CL0009011
    CSI 2.03
    rCSI 2.39%
    PRS 96.48
  • common dendritic progenitor CL0001029
    CSI 1.96
    rCSI 2.46%
    PRS 98.22
  • basal cell CL0000646
    CSI 1.79
    rCSI 2.39%
    PRS 94.26
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.04
    rCSI 2.53%
    PRS 87.65
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.63
    rCSI 2.26%
    PRS 87.86
  • erythroid progenitor cell CL0000038
    CSI 0.5
    rCSI 2.85%
    PRS 97.08
  • direct pathway medium spiny neuron CL4023026
    CSI 0.3
    rCSI 7.23%
    PRS 87.17
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.3
    rCSI 7.27%
    PRS 86.9

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [PUS1](/details-gene/80324), or Pseudouridine Synthase 1, is a protein-coding gene located on chromosome 12q24.33 that encodes a key RNA-modifying enzyme. This enzyme catalyzes the isomerization of uridine to pseudouridine at specific positions in transfer RNAs (tRNAs) and other RNA molecules. It exhibits broad subcellular localization, functioning within the nucleus, cytoplasm, and notably, the mitochondrial matrix. Its primary role in ensuring proper tRNA structure and function is critical for translational efficiency and fidelity. Reflecting its fundamental role in protein synthesis, [PUS1](/details-gene/80324) shows significant expression in metabolically active cells and progenitor populations, particularly hematopoietic progenitors such as the [common myeloid progenitor](/details-cell/CL0000049). Clinically, loss-of-function mutations in [PUS1](/details-gene/80324) are causative for Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA), an autosomal recessive disorder ([600462](https://omim.org/entry/600462)), underscoring its essential, non-redundant function in mitochondrial biology and hematopoiesis. ## Cellular Roles and Expression Landscape The expression profile of [PUS1](/details-gene/80324) suggests it is a crucial enzyme for cells undergoing differentiation, proliferation, or high metabolic activity. **Overall**, its significance is highest in hematopoietic progenitor cells, including [common myeloid progenitor](/details-cell/CL0000049), [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050), and [granulocyte monocyte progenitor cell](/details-cell/CL0000557). This pattern is highly consistent with the clinical manifestation of sideroblastic anemia in patients with [PUS1](/details-gene/80324) mutations, as these progenitors require robust translational capacity to support the massive production of lineage-specific proteins. Beyond hematopoiesis, [PUS1](/details-gene/80324) is also highly significant in other active cell populations. These include professional antigen-presenting cells like the [plasmacytoid dendritic cell, human](/details-cell/CL0001058), and various epithelial or high-turnover cells such as the [keratinocyte](/details-cell/CL0000312), [hepatocyte](/details-cell/CL0000182), and [transit amplifying cell of colon](/details-cell/CL0009011). This suggests a broad role in maintaining tissue homeostasis where efficient protein synthesis is paramount for cell function and renewal. In contrast, the gene's significance is notably lower in more terminally differentiated, post-mitotic cells like the [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) and [direct pathway medium spiny neuron](/details-cell/CL4023026), indicating that while ubiquitously expressed, its role is most pronounced in cells with high biosynthetic demands. ## Pathways and Molecular Function The functions of [PUS1](/details-gene/80324) are centered on RNA modification, a fundamental process for gene expression regulation. Gene Ontology annotations confirm its role in [pseudouridine synthase activity](/details-go/GO:0009982), with a specificity for tRNAs ([tRNA pseudouridine(38-40) synthase activity](/details-go/GO:0160147)). The enzyme binds RNA ([RNA binding](/details-go/GO:0003723)), particularly tRNA ([tRNA binding](/details-go/GO:0000049)), to perform its catalytic function. Reactome pathway analysis places [PUS1](/details-gene/80324) within the broader context of [Metabolism of RNA](/details-pathway/R-HSA-8953854) and, more specifically, [tRNA processing](/details-pathway/R-HSA-72306). Its dual localization is reflected by its involvement in both [tRNA modification in the nucleus and cytosol](/details-pathway/R-HSA-6782315) and [tRNA modification in the mitochondrion](/details-pathway/R-HSA-6787450). This mitochondrial function is critical for understanding its pathology; the modification of mitochondrial tRNAs ([mitochondrial tRNA pseudouridine synthesis](/details-go/GO:0070902)) is essential for the translation of mitochondrially-encoded proteins that form core subunits of the electron transport chain. Defective mitochondrial translation due to loss of [PUS1](/details-gene/80324) function directly leads to the mitochondrial myopathy and lactic acidosis observed in MLASA patients ([Link](https://doi.org/10.1086/421530), [Link](https://doi.org/10.1074/jbc.m500216200)). ## Research Directions The established link between [PUS1](/details-gene/80324) deficiency and MLASA provides a strong foundation for further investigation into the precise mechanisms of disease and the gene's broader physiological roles. **Testable Hypotheses:** 1. The high expression of [PUS1](/details-gene/80324) in hematopoietic progenitors, coupled with the sideroblastic anemia phenotype, suggests that PUS1-mediated modification of specific mitochondrial or cytosolic tRNAs is a rate-limiting step for the translation of key proteins in erythropoiesis, such as globin chains and ferrochelatase. Loss of these modifications may lead to ribosomal stalling and inefficient protein synthesis, causing iron accumulation and defective red blood cell maturation. 2. Given its high expression in [keratinocyte](/details-cell/CL0000312) and other renewing epithelia, [PUS1](/details-gene/80324) may play a crucial, yet uncharacterized, role in skin and gut homeostasis. It is hypothesized that reduced [PUS1](/details-gene/80324) function could sensitize these tissues to stress (e.g., UV radiation, inflammatory stimuli) by impairing the translational capacity required for an effective stress response and cellular repair. **Proposed Experimental Approach:** To test the first hypothesis, one could utilize a CRISPR-Cas9 base editing approach to introduce known pathogenic [PUS1](/details-gene/80324) mutations into human CD34+ hematopoietic stem and progenitor cells. These edited cells would then be differentiated *in vitro* towards the erythroid lineage. The impact on erythropoiesis could be assessed by quantifying hemoglobinization (benzidine staining), erythroid surface marker expression (e.g., CD71, CD235a) via flow cytometry, and the formation of ring sideroblasts (Perls' Prussian blue stain). Furthermore, ribosome profiling (Ribo-Seq) combined with quantitative proteomics on differentiated erythroblasts would identify specific codons or transcripts that experience translational stalling, directly linking the loss of tRNA pseudouridylation to defects in the synthesis of proteins critical for red blood cell development. **Therapeutic Potential:** As MLASA is an autosomal recessive loss-of-function disorder, the therapeutic strategy for [PUS1](/details-gene/80324) is focused on restoration or activation, not inhibition. Given the severe hematopoietic and systemic defects, [PUS1](/details-gene/80324) represents a prime candidate for gene replacement therapy. An *ex vivo* approach, where a patient's own hematopoietic stem cells are harvested, corrected with a functional copy of the [PUS1](/details-gene/80324) gene using a lentiviral or AAV vector, and then re-infused, could potentially provide a curative treatment for the hematological and systemic aspects of the disease. Any strategy involving inhibition of [PUS1](/details-gene/80324) would be contraindicated.

Genular Protein ID: 3455629245

Symbol: PUS1_HUMAN

Name: tRNA pseudouridine(38-40) synthase

UniProtKB Accession Codes:

Q9Y606 A8K877 B3KQC1 Q8WYT2 Q9BU44

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 6 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 7 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 15 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 2 RefSeq 3 Rhea 9 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 15498874

Title: Large-scale cDNA transfection screening for genes related to cancer development and progression.

PubMed ID: 15498874

DOI: 10.1073/pnas.0404089101

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 10094309

Title: Cloning and characterization of a mammalian pseudouridine synthase.

PubMed ID: 10094309

DOI: 10.1017/s1355838299981591

PubMed ID: 15108122

Title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).

PubMed ID: 15108122

DOI: 10.1086/421530

PubMed ID: 15772074

Title: Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.

PubMed ID: 15772074

DOI: 10.1074/jbc.m500216200

PubMed ID: 15971356

Title: Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: an autosomal recessive syndrome in Persian Jews caused by a mutation in the PUS1 gene.

PubMed ID: 15971356

DOI: 10.1177/08830738050200051301

PubMed ID: 17081983

Title: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

PubMed ID: 17081983

DOI: 10.1016/j.cell.2006.09.026

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 17056637

Title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).

PubMed ID: 17056637

DOI: 10.1136/jmg.2006.045252

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19413330

Title: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.

PubMed ID: 19413330

DOI: 10.1021/ac9004309

PubMed ID: 21686963

Title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).

PubMed ID: 21686963

DOI: 10.1136/bcr.05.2009.1889

PubMed ID: 19731322

Title: Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations.

PubMed ID: 19731322

DOI: 10.1002/pbc.22244

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 25227147

Title: Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood.

PubMed ID: 25227147

DOI: 10.1038/ejhg.2014.192

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 26556812

Title: Clinical and molecular study in a long-surviving patient with MLASA syndrome due to novel PUS1 mutations.

PubMed ID: 26556812

DOI: 10.1007/s10048-015-0465-x

PubMed ID: 28832011

Title: A myopathy, lactic acidosis, sideroblastic anemia (MLASA) case due to a novel PUS1 mutation.

PubMed ID: 28832011

DOI: 10.4274/tjh.2017.0231

PubMed ID: 31477916

Title: mRNA structure determines modification by pseudouridine synthase 1.

PubMed ID: 31477916

DOI: 10.1038/s41589-019-0353-z

PubMed ID: 32287105

Title: A novel PUS1 mutation in 2 siblings with MLASA syndrome: a review of the literature.

PubMed ID: 32287105

DOI: 10.1097/mph.0000000000001806

PubMed ID: 35051350

Title: Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing.

PubMed ID: 35051350

DOI: 10.1016/j.molcel.2021.12.023

PubMed ID: 23707380

Title: In human pseudouridine synthase 1 (hPus1), a C-terminal helical insert blocks tRNA from binding in the same orientation as in the Pus1 bacterial homologue TruA, consistent with their different target selectivities.

PubMed ID: 23707380

DOI: 10.1016/j.jmb.2013.05.014

PubMed ID: 24722331

Title: Steroid receptor RNA activator (SRA) modification by the human pseudouridine synthase 1 (hPus1p): RNA binding, activity, and atomic model.

PubMed ID: 24722331

DOI: 10.1371/journal.pone.0094610

Sequence Information:

  • Length: 427
  • Mass: 47470
  • Checksum: ACE9FA6AE0F178BA
  • Sequence:
    • MGLQLRALLG AFGRWTLRLG PRPSCSPRMA GNAEPPPAGA ACPQDRRSCS GRAGGDRVWE 
DGEHPAKKLK SGGDEERREK PPKRKIVLLM AYSGKGYHGM QRNVGSSQFK TIEDDLVSAL 
VRSGCIPENH GEDMRKMSFQ RCARTDKGVS AAGQVVSLKV WLIDDILEKI NSHLPSHIRI 
LGLKRVTGGF NSKNRCDART YCYLLPTFAF AHKDRDVQDE TYRLSAETLQ QVNRLLACYK 
GTHNFHNFTS QKGPQDPSAC RYILEMYCEE PFVREGLEFA VIRVKGQSFM MHQIRKMVGL 
VVAIVKGYAP ESVLERSWGT EKVDVPKAPG LGLVLERVHF EKYNQRFGND GLHEPLDWAQ 
EEGKVAAFKE EHIYPTIIGT ERDERSMAQW LSTLPIHNFS ATALTAGGTG AKVPSPLEGS 
EGDGDTD

Genular Protein ID: 3211093834

Symbol: E5KMT6_HUMAN

Name: N/A

UniProtKB Accession Codes:

E5KMT6

Database IDs:

ARBA 3 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 41 ExpressionAtlas 1 GO 6 Gene3D 2 InterPro 6 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OrthoDB 1 PANTHER 2 PIRSR 2 Pfam 2 RefSeq 2 SAM 1 SMR 1 SUPFAM 1 VEuPathDB 1

Citations:

PubMed ID: 20843780

Title: Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing.

PubMed ID: 20843780

DOI: 10.1093/nar/gkq750

Sequence Information:

  • Length: 399
  • Mass: 44377
  • Checksum: 56F36851979AFE3B
  • Sequence:
    • MAGNAEPPPA GAACPQDRRS CSGRAGGDRV WEDGEHPAKK LKSGGDEERR EKPPKRKIVL 
LMAYSGKGYH GMQRNVGSSQ FKTIEDDLVS ALVRSGCIPE NHGEDMRKMS FQRCARTDKG 
VSAAGQVVSL KVWLIDDILE KINSHLPSHI RILGLKRVTG GFNSKNRCDA RTYCYLLPTF 
AFAHKDRDVQ DETYRLSAET LQQVNRLLAC YKGTHNFHNF TSQKGPQDPS ACRYILEMYC 
EEPFVREGLE FAVIRVKGQS FMMHQIRKMV GLVVAIVKGY APESVLERSW GTEKVDVPKA 
PGLGLVLERV HFEKYNQRFG NDGLHEPLDW AQEEGKVAAF KEEHIYPTII GTERDERSMA 
QWLSTLPIHN FSATALTAGG TGAKVPSPLE GSEGDGDTD