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Aliases | DUT , dUTPase, deoxyuridine triphosphatase | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 601266 MGI: 1346051 HomoloGene: 31475 GeneCards: DUT | ||||||||||||||||||||||||||||||||||||||||||||||||||
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DUTP pyrophosphatase, also known as DUT, is an enzyme which in humans is encoded by the DUT gene on chromosome 15. [5]
This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotrimeric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19. [5]
In humans, this gene encodes a homotrimeric enzyme with two isoforms characterized by their distinct subcellular localizations: the nuclear isoform (DUT-N) and mitochondrial isoform (DUT-M). [6] [7] [8]
Northern blot analysis reveals distinct mRNA transcripts for DUT-N (1.1 kb) and DUT-M (1.4 kb). [7] The isoforms are produced from alternative splicing at different 5' exons, with the first exon of DUT-N occurring 767 base pairs downstream of the first exon in DUT-M. [7] [8] Regulation at different promoters has been proposed to account for the differential expression of these isoforms. [7]
The mature forms of DUT-N (22 kDa) and DUT-M (23 kDa) are nearly identical except for a short N-terminal region present in DUT-M. The DUT-M precursor (31 kDa) contains an arginine-rich, 69-residue mitochondrial targeting sequence which undergoes post-translational cleavage to effect mitochondrial import. [6] [7] [8] Meanwhile, the monopartite NLS sequence is critical for the function and nuclear localization of DUT-N, which would otherwise accumulate in the cytoplasm. [6] [8] Though both isoforms contain the NLS, the sequence in DUT-M is sequestered away from cognate karyopherins. [6] The isoelectric points of DUT-N (6.0) and DUT-M (8.1) correspond to the pH of their respective subcellular compartments. [7]
DUT is a homotrimer with three active sites formed by each of its three subunits. [8] Typically, each subunit forms an eight-stranded barrel that swaps C-terminal β-strands with the other subunits to assemble into the trimer structure. In addition to the β-strand swapping, these subunits interact via extended bimolecular interfaces and three-fold central channel. [9] As a member of the dUTPase family, DUT requires the presence of a divalent metal ion such as Mg2+ for their enzymatic function. [10] DUT-N also contains a consensus cyclin-dependent kinase phosphorylation site that is phosphorylated at the serine as part of its cell cycle regulation. [7]
DUT is a member of the dUTPase family, which is known for catalyzing the pyrophosphoralysis of dUTP into dUMP and inorganic pyrophosphate. This function contributes to DNA replication and repair via de novo thymidylate biosynthesis, as the dUMP product is methylated by thymidylate synthase (TS) to form dTMP, which is then phosphorylated to dTTP. [6] [7] [8] [11] DUT is also crucial for maintaining genome integrity by reducing cellular dUTP levels, thereby preventing the repeated cycles of uracil misincorporation into DNA and DNA repair-mediated strand breaks that would lead to cell death. [6] [7] [8] [10] [11]
In addition to their different localizations, the two DUT isoforms display different expression patterns: while DUT-M is constitutively expressed, DUT-N is under cell cycle control and notably upregulated during S phase. [6] [7] These expression patterns correspond with their roles in the DNA replication cycle of their respective genomes, and thus indicate different regulatory mechanisms affecting each isoform. [7]
The dUTP hydrolysis cycle can be outlined in the following four enzymatic steps: (i) fast substrate binding, (ii) isomerization of the enzyme-substrate complex into the catalytically competent conformation, (iii) hydrolysis of the substrate, and (iv) rapid, non-ordered release of the products. [12]
Since many chemotherapeutic agents such as 5-fluorouracil treat neoplastic diseases, including head and neck cancer, breast cancer, and gastrointestinal cancer, by targeting TS in thymidylate metabolism, DUT may protect against the cytotoxic side effects by countering dUTP accumulation. [7] [8] [11] [13] [14] At the same time, high levels of DUT-N have been associated with chemoresistance and faster tumor progression, and thus, could also serve as a prognostic marker for overall survival and response to chemotherapy. [7] [8] [11] [12] [13] Similarly, DUT is significantly overexpressed in hepatocellular carcinoma and may serve as a prognostic marker for the cancer. [15] Notably, DUT expression is regulated by the tumor suppressor gene p53 in order to promote apoptosis of tumor cells.<pmid19015155/> Abnormal DUT expression and localization has been speculated to promote cancer transformation. [8]
DUT interacts with dUTP to catalyze its hydrolysis into dUMP and pyrophosphate. [5] E2F and Sp1 enhance DUT expression by binding its promoter, while p53 inhibits DUT transcription by binding its promoter. A putative NF-κB binding site was also identified in the DUT promoter. [14]
Uracil is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine (T). Uracil is a demethylated form of thymine.
DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.
8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the OGG1 gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species.
dnaS or dut is a gene involved in DNA replication in Escherichia coli. It encodes dUTP nucleotidohydrolase, an enzyme responsible for catalyzing the conversion of dUTP to dUMP, thereby ensuring that the organism's DNA contains the nucleobase thymine instead of uracil.
Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor -like 1" which has an official symbol of NFE2L1.
DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.
In Enzymology, a dUTP diphosphatase (EC 3.6.1.23) is an enzyme that catalyzes the chemical reaction
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Cyclin-O is a protein that in humans is encoded by the CCNO gene.
Folylpolyglutamate synthase, mitochondrial is an enzyme that in humans is encoded by the FPGS gene.
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Cytochrome c oxidase subunit 6A1, mitochondrial is a protein that in humans is encoded by the COX6A1 gene. Cytochrome c oxidase 6A1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. A mutation of the COX6A1 gene is associated with a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
Phosphatidate cytidylyltransferase 1 is an enzyme that in humans is encoded by the CDS1 gene.
TCAIM is a protein that in humans is encoded by the TCAIM gene.
ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.
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5',3'-nucleotidase, mitochondrial, also known as 5'(3')-deoxyribonucleotidase, mitochondrial (mdN) or deoxy-5'-nucleotidase 2 (dNT-2), is an enzyme that in humans is encoded by the NT5M gene. This gene encodes a 5' nucleotidase that localizes to the mitochondrial matrix. This enzyme dephosphorylates the 5'- and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides. The gene is located within the Smith–Magenis syndrome region on chromosome 17.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.