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Literature summary for 3.6.1.12 extracted from
- DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools (2019), Cell. Mol. Life Sci., 77, 1645-1660 .
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | DCTPP1 counteracts the cytotoxic effect of the antitumoral demethylating agent decitabine (5-aza-deoxycytidine) by removing 5-aza-dCTP from the nucleotide pool and is being studied as a potential drug target to improve decitabine-based chemotherapy | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | construction of DCTPP1-deficient MCF-7 cells, which exhibit increased uracil misincorporation and an activation of the DNA damage response. Downregulation of DCTPP1 expression impairs proliferation and perturbs the dNTP pool of MCF-7 cells. Modulation of the dUTP/dTTP ratio reduces genomic instability. The downregulation of DCTPP1 has profound consequences on cell cycle progression, nucleotide pools. Phneotype of a bona fide DCTPP1-knockout (DCTPP1-KO) cell line derived from the HAP1 cell line, overview. HAP1 is a near haploid human cell line that is derived from the male chronic myelogenous leukemia (CML) cell line KBM-7, and deletion in exon 2 of the DCTPP1 gene is generated using the CRISPR/Cas9 technology. No differences in the pool of dGTP are observed between HAP1 wild-type and DCTPP1-KO cell lines. dUTP pool with potential genotoxic consequences is exclusively detected in deficient cells. The dCTP pool is similar for HAP1 wild-type and DCTPP1-KO cell lines. DCTPP1-knockout cells exhibit normal proliferation in spite of an imbalanced nucleotide pool. DCTPP1-KO cells exhibit a hypermutator phenotype. The activation of the DNA damage response upon DCTPP1 inactivation can be reverted by the expansion of the dTTP pool or defects in uracil excision. Phenotypes, detailed overview | Homo sapiens |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | - |
Homo sapiens | 5829 | - |
| mitochondrion | - |
Homo sapiens | 5739 | - |
| nucleus | - |
Homo sapiens | 5634 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| dCTP + H2O | Homo sapiens | - |
dCMP + diphosphate | - |
? |  |
| additional information | Homo sapiens | human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is a dNTP pyrophosphatase with high affinity for dCTP and 5'-modified dCTP derivatives | ? | - |
- |
|
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q9H773 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| additional information | DCTPP1 is highly expressed in embryonic and proliferative tissues with an expanded nucleotide pool. The enzyme is also upregulated in multiple human carcinomas and cancer stem cells | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| dCTP + H2O | - |
Homo sapiens | dCMP + diphosphate | - |
? | |
| additional information | human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is a dNTP pyrophosphatase with high affinity for dCTP and 5'-modified dCTP derivatives | Homo sapiens | ? | - |
- |
|
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| all-alpha dCTP pyrophosphatase 1 | - |
Homo sapiens |
| all-alpha NTP pyrophosphatase | - |
Homo sapiens |
| dCTP pyrophosphatase 1 | UniProt | Homo sapiens |
| DCTPP1 | - |
Homo sapiens |
| NTP pyrophosphohydrolase | - |
Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | nucleotide pools and the dUTP/dTTP ratio are severely altered in DCTPP1-deficient cells, which exhibit an accumulation of uracil in genomic DNA, the activation of the DNA damage response and both a mitochondrial and nuclear hypermutator phenotype. DNA damage can be reverted by incubation with thymidine, dUTPase overexpression or uracil-DNA glycosylase suppression. Moreover, DCTPP1-deficient cells are highly sensitive to downregulation of nucleoside salvage. DCTPP1-deficient cells accumulate high levels of dCTP and are hypersensitive to exposure to the nucleoside analogues 5-iodo-2'-deoxycytidine and 5-methyl-2'-deoxycytidine. Downregulation of DCTPP1 expression impairs proliferation and perturbs the dNTP pool of MCF-7 cells. DCTPP1-deficient cells are more prone to uracil misincorporation and exhibit an activated DNA damage response (DDR), altered cell cycle progression, and a mutator phenotype that affects both chromosomal and mitochondrial DNA (mtDNA) | Homo sapiens |
| physiological function | To maintain dNTP pool homeostasis and preserve genetic integrity of nuclear and mitochondrial genomes, the synthesis and degradation of DNA precursors must be precisely regulated. Central role for DCTPP1 in the homeostasis of dCTP, dTTP and dUTP. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is a dNTP pyrophosphatase with high affinity for dCTP and 5'-modified dCTP derivatives. DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing another player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity. DCTPP1 catalyzes the hydrolysis of dCTP into dCMP and diphosphate keeping the cellular dCTP pool balanced. DCTPP1 can also hydrolyze in vitro C5-modified dNTPs such as 5-halogenated, 5-methyl and 5-formyl deoxycytidine, and therefore may have an additional house-cleaning function. Central role of DCTPP1 in the formation of dCMP for dTMP biosynthesis | Homo sapiens |
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