Details for: NUDT15

Gene ID: 55270

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: NUDT15

Ensembl ID: ENSG00000136159

Description: nudix hydrolase 15

Cell Significance Landscape

Associated with

Significant Cells

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

  • perivascular cell CL4033054
    CSI 3.44
    rCSI 4.7%
    PRS 97.19
  • early lymphoid progenitor CL0000936
    CSI 3.18
    rCSI 2.79%
    PRS 97.32
  • common myeloid progenitor CL0000049
    CSI 3.15
    rCSI 2.55%
    PRS 96.15
  • neural crest cell CL0011012
    CSI 3.07
    rCSI 2.42%
    PRS 91.43
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 3.03
    rCSI 3.5%
    PRS 89.98
  • epithelial cell of lower respiratory tract CL0002632
    CSI 2.97
    rCSI 2.3%
    PRS 96.73
  • placental villous trophoblast CL2000060
    CSI 2.93
    rCSI 4.53%
    PRS 93.97
  • ciliated epithelial cell CL0000067
    CSI 2.62
    rCSI 2.3%
    PRS 89.23
  • extravillous trophoblast CL0008036
    CSI 2.6
    rCSI 3.22%
    PRS 94
  • stem cell CL0000034
    CSI 2.56
    rCSI 2.47%
    PRS 93.22
  • multi-ciliated epithelial cell CL0005012
    CSI 2.52
    rCSI 2.52%
    PRS 91.31
  • colon epithelial cell CL0011108
    CSI 2.48
    rCSI 2.59%
    PRS 93.6
  • retina horizontal cell CL0000745
    CSI 2.47
    rCSI 3.76%
    PRS 93.2
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.37
    rCSI 2.05%
    PRS 96.35
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.17
    rCSI 1.96%
    PRS 94.69
  • podocyte CL0000653
    CSI 2.12
    rCSI 9.41%
    PRS 95.27
  • radial glial cell CL0000681
    CSI 2.11
    rCSI 2.93%
    PRS 94.21
  • fallopian tube secretory epithelial cell CL4030006
    CSI 2.11
    rCSI 2.03%
    PRS 94.32
  • retinal cone cell CL0000573
    CSI 2
    rCSI 3.22%
    PRS 89.75
  • retinal blood vessel endothelial cell CL0002585
    CSI 1.94
    rCSI 3.1%
    PRS 96.79
  • transit amplifying cell of colon CL0009011
    CSI 1.94
    rCSI 2.27%
    PRS 95.36
  • club cell CL0000158
    CSI 1.9
    rCSI 2.79%
    PRS 92.74
  • basal cell CL0000646
    CSI 1.74
    rCSI 2.32%
    PRS 93.27
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.67
    rCSI 2.94%
    PRS 87.02
  • colon goblet cell CL0009039
    CSI 1.47
    rCSI 3.49%
    PRS 95.84
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.23
    rCSI 3.31%
    PRS 96.11
  • transit amplifying cell of small intestine CL0009012
    CSI 0.88
    rCSI 3.88%
    PRS 96.65
  • erythroid progenitor cell CL0000038
    CSI 0.44
    rCSI 2.5%
    PRS 96.32
  • pluripotent stem cell CL0002248
    CSI 0.23
    rCSI 6.77%
    PRS 97.56

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 [NUDT15](/details-gene/55270) (Nudix Hydrolase 15) is a protein-coding gene located on chromosome 13q14.2 that encodes a "housekeeping" enzyme responsible for hydrolyzing nucleoside diphosphates, particularly oxidized purine nucleotides. Its primary function is to prevent the misincorporation of damaged nucleotides into DNA, thereby maintaining genomic integrity ([Link](https://doi.org/10.1074/jbc.271.41.25059)). **Overall**, expression data indicates that [NUDT15](/details-gene/55270) is a significant gene in various progenitor and stem cell populations, including [early lymphoid progenitor](/details-cell/CL0000936)s and [common myeloid progenitor](/details-cell/CL0000049)s, as well as in specialized, high-turnover tissues like the respiratory and colonic epithelium. Clinically, [NUDT15](/details-gene/55270) has gained prominence for its role in pharmacogenomics, as common genetic variants are strongly associated with severe hematopoietic toxicity in patients treated with thiopurine drugs ([Link](https://doi.org/10.1038/ng.3060), [Link](https://doi.org/10.1038/ng.3508)). ## Cellular Roles and Expression Landscape The expression profile of [NUDT15](/details-gene/55270) highlights its fundamental role in cellular maintenance, particularly in highly proliferative or metabolically active cell types. **Overall**, the gene shows the highest significance in progenitor cell populations, including [early lymphoid progenitor](/details-cell/CL0000936), [common myeloid progenitor](/details-cell/CL0000049), [granulocyte monocyte progenitor cell](/details-cell/CL0000557), and [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050). This pattern is consistent with its function in safeguarding DNA integrity during rapid cell division, a critical process for hematopoietic development. Beyond progenitor cells, [NUDT15](/details-gene/55270) is also highly significant in several specialized differentiated cell types. These include [perivascular cell](/details-cell/CL4033054)s, various trophoblast populations ([placental villous trophoblast](/details-cell/CL2000060), [extravillous trophoblast](/details-cell/CL00008036)), and multiple types of epithelial cells such as [epithelial cell of lower respiratory tract](/details-cell/CL0002632), [ciliated epithelial cell](/details-cell/CL0000067), and [colon epithelial cell](/details-cell/CL0011108). This broad expression in tissues with high cell turnover or exposure to potential mutagens underscores its role as a key enzyme for maintaining genome stability across diverse cellular contexts. ## Pathways and Molecular Function The functional annotations for [NUDT15](/details-gene/55270) confirm its role as a pyrophosphatase involved in nucleotide metabolism and DNA protection. Its molecular functions are centered on hydrolyzing oxidized purine nucleotides, such as its '[8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity](/details-go/GO:0035539)', which prevents the incorporation of the highly mutagenic 8-oxo-dGTP into DNA. This activity is a core part of biological processes like '[Dna protection](/details-go/GO:0042262)' and '[Purine nucleotide catabolic process](/details-go/GO:0006195)'. From a systems biology perspective, [NUDT15](/details-gene/55270) is a key component of the '[Phosphate bond hydrolysis by NUDT proteins](/details-pathway/R-HSA-2393930)' and '[Nucleotide catabolism](/details-pathway/R-HSA-8956319)' pathways. Its clinical importance is directly reflected in its involvement in the '[Azathioprine adme](/details-pathway/R-HSA-9748787)' pathway. Thiopurine drugs, such as azathioprine, are converted into active thioguanine nucleotide (TGN) analogues. [NUDT15](/details-gene/55270) can deactivate these TGNs by converting them from triphosphates to monophosphates, preventing their incorporation into DNA and subsequent cytotoxicity. Genetic variants that reduce or abolish [NUDT15](/details-gene/55270) enzyme activity lead to the accumulation of TGNs, causing severe bone marrow suppression ([Link](https://doi.org/10.1038/ng.3508)). ## Research Directions The established role of [NUDT15](/details-gene/55270) in thiopurine metabolism provides a strong foundation for further research into its broader physiological functions and therapeutic implications. **Proposed Hypotheses:** 1. The high significance of [NUDT15](/details-gene/55270) in hematopoietic progenitor cells ([early lymphoid progenitor](/details-cell/CL0000936), [common myeloid progenitor](/details-cell/CL0000049)) suggests that hypomorphic variants, even in the absence of drug exposure, may subtly impair hematopoietic stem cell fitness and contribute to bone marrow stress responses or aging phenotypes. 2. Given its expression in barrier tissues like the respiratory and colon epithelium ([epithelial cell of lower respiratory tract](/details-cell/CL0002632), [colon epithelial cell](/details-cell/CL0011108)), loss-of-function variants in [NUDT15](/details-gene/55270) could increase susceptibility to mutagenesis from environmental or inflammatory-induced oxidative stress, potentially elevating the risk for conditions like inflammatory bowel disease or certain cancers. **Key Experimental Approach:** To test the hypothesis regarding hematopoietic fitness (Hypothesis 1), a robust experimental approach would involve using CRISPR-Cas9 base editing to introduce clinically relevant [NUDT15](/details-gene/55270) risk variants (e.g., p.Arg139Cys) into primary human hematopoietic stem and progenitor cells (HSPCs). These engineered HSPCs, alongside isogenic wild-type controls, could then be subjected to competitive transplantation assays in immunodeficient mice. Long-term engraftment and lineage output could be monitored via flow cytometry to determine if the [NUDT15](/details-gene/55270) variants confer a cell-intrinsic disadvantage in hematopoietic reconstitution, even without thiopurine challenge. **Therapeutic Potential:** The primary therapeutic relevance of [NUDT15](/details-gene/55270) is not as a direct drug target for inhibition or activation, but as a critical biomarker for personalized medicine. Genotyping for [NUDT15](/details-gene/55270) variants prior to initiating thiopurine therapy is becoming standard practice to guide dosing and prevent life-threatening myelosuppression. This pharmacogenomic application is a clear example of how understanding a single gene's function can directly translate to improved patient safety and treatment efficacy. Further research could explore if [NUDT15](/details-gene/55270) status influences the efficacy or toxicity of other nucleotide-analogue chemotherapies.

Genular Protein ID: 3077549325

Symbol: NUD15_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q9NV35 A2RUR6 Q32Q27 Q6P2C9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 19 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EC 2 EMBL 7 Ensembl 1 EvolutionaryTrace 1 GO 15 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 2 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 13 PDBsum 13 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 2 Rhea 6 SABIO-RK 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15057823

Title: The DNA sequence and analysis of human chromosome 13.

PubMed ID: 15057823

DOI: 10.1038/nature02379

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: 8810257

Title: The MutT proteins or 'Nudix' hydrolases, a family of versatile, widely distributed, 'housecleaning' enzymes.

PubMed ID: 8810257

DOI: 10.1074/jbc.271.41.25059

PubMed ID: 19419956

Title: Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2.

PubMed ID: 19419956

DOI: 10.1074/jbc.m109.015289

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22556419

Title: Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2.

PubMed ID: 22556419

DOI: 10.1074/jbc.m112.363010

PubMed ID: 25108385

Title: A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.

PubMed ID: 25108385

DOI: 10.1038/ng.3060

PubMed ID: 26878724

Title: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

PubMed ID: 26878724

DOI: 10.1038/ng.3508

PubMed ID: 26238318

Title: Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2.

PubMed ID: 26238318

DOI: 10.1038/ncomms8871

Sequence Information:

  • Length: 164
  • Mass: 18609
  • Checksum: 9FF20DA411C9E9C7
  • Sequence:
    • MTASAQPRGR RPGVGVGVVV TSCKHPRCVL LGKRKGSVGA GSFQLPGGHL EFGETWEECA 
QRETWEEAAL HLKNVHFASV VNSFIEKENY HYVTILMKGE VDVTHDSEPK NVEPEKNESW 
EWVPWEELPP LDQLFWGLRC LKEQGYDPFK EDLNHLVGYK GNHL