modulation of nucleotide pools

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All cells from bacteria to humans are equipped with phosphohydrolases that hydrolyse triphosphates of damaged nucleotides to monophosphates. Nucleotide monophosphate kinases can discriminate between damaged and unchanged nucleotides, and damaged nucleotides are not re-circulated to cellular pool of nucleoside triphosphates, but instead they are dephosphorylated by nucleotidases and extruded from the cell, which prevents their incorporation into DNA by DNA polymerases.

Escherichia coli MutT protein, is a pyrophosphohydrolase (e.g. 8-oxodGTPase) and has a high specificity for its substrates, 8-oxoG-containing nucleotides (8-oxo-dGTP, 8-oxo-dGDP, 8-oxo-GTP and 8-oxo-GDP), and catalyzes their hydrolysis to the corresponding nucleoside monophosphates. These 8-oxoG-containing nucleotides are available for DNA or RNA synthesis because 8-oxo-dGDP and 8-oxo-GDP are readily phosphorylated to generate 8-oxo-dGTP and 8-oxo-GTP, respectively. In this way, MutT strongly avoids replicational and transcriptional errors caused by 8-oxoG Importance of 8-oxodGTP removal from nucleotide pool is highlighted by the fact that E.coli mutT mutant has 1000-fold increased spontaneous mutation rate in comparison to the wild type strain.
Mammalian cells also have enzymes capable of eliminating 8-oxoG-containing nucleotides from the nucleotide pool. These include MTH1, MTH2 and NUDT5, which have broad substrate specificity for various oxidized nucleotides. Human MTH1 (hMTH1) catalyzes the hydrolysis of 8-oxo-dGTP, 2-oxo-dATP, 2-oxo-ATP, 8-oxo-dATP and 8-oxo-GTP. Human NUDT5 (hNUDT5) hydrolyzes 8-oxo-dGDP, 8-oxo-GDP, 8-oxo-dADP, 2-oxo-dADP and 5-CHO-dUDP into their corresponding nucleoside monophosphates and inorganic phosphates (Pi). Since 8-oxo-dGDP inhibits hMTH1 activity, the catalytic activity of hNUDT5 also results in the promotion of hMTH1 activity as well as in a reduction in the amount of 8-oxo-dGTP generated from 8-oxo-dGDP by nucleoside diphosphate kinase. Thus, hNUDT5 has a role in preventing replicational and transcriptional errors in human cells. 

In E.coli and yeast dUTPase activity, which removes dUTP from nucleotide pool is also known. E.coli dut mutants reveal strong hypermutatory phenotype, showing that incorporation of dUTP from nucleotide pool is a powerful source of genomic instability.
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ORTHOLOGY CLASS Homo sapiens L. (human) [HSA] Mus musculus L. (mouse) [MMU] Caenorhabditis elegans Maupas (nematode) [CEL] Drosophila melanogaster Meigen (fruit fly) [DME] Saccharomyces cerevisiae Meyen ex E.C. Hansen (budding yeast) [SCE] Schizo-saccharomyces pombe Lindner (fission yeast) [SPO] Escherichia coli Migula (bacterium) K-12 MG1655 [ECO] Arabidopsis thaliana (L.) Heynh. (mouse-ear cress) [ATH]
ko:K10808 (ribonucleoside-diphosphate reductase subunit M2 [EC:1.17.4.1]) RRM2B
RRM2
Rrm2
Rrm2b
rnr-2 RnrS RNR2
RNR4
suc22 RNR2A
TSO2
ko:K10807 (ribonucleoside-diphosphate reductase subunit M1 [EC:1.17.4.1]) RRM1 Rrm1 rnr-1 RnrL RNR3
RNR1
cdc22 RNR1
ko:K00526 (ribonucleoside-diphosphate reductase beta chain [EC:1.17.4.1]) gi:17567153 nrdF
nrdB
ko:K00525 (ribonucleoside-diphosphate reductase alpha chain [EC:1.17.4.1]) nrdA
nrdE
ko:K01520 (dUTP pyrophosphatase [EC:3.6.1.23]) DUT Dut dut-1 dUTPase DUT1 gi:19114785 dut gi:15232681
ko:K03574 (7,8-dihydro-8-oxoguanine triphosphatase [EC:3.6.1.-]) NUDT1 (MTH1) Nudt1 MutT NUDT1

Last modification date: Oct. 5, 2011