The NTP pyrophosphatase DCTPP1 contributes to the homeostasis and cleansing of the dNTP pool in human cells

The size and composition of deoxyribonucleotide (dNTP) pools influence the accuracy of DNA synthesis and consequently the genetic stability of nuclear and mitochondrial genomes. In order to keep the dNTP pool in balance, the synthesis and degradation of DNA precursors must be precisely regulated. One of such mechanisms involves catabolic activities that convert deoxynucleoside triphosphates into their monophosphate form. Human cells possess an all-alpha NTP pyrophosphatase named DCTPP1 (also known as XTP3-TPA). Here, we provide an extensive characterization of this enzyme which is ubiquitously distributed in the nucleus, cytosol and mitochondria. Interestingly, we found that in addition to dCTP, methyl-dCTP and 5-halogenated nucleotides, DCTPP1 hydrolyzes 5-formyl-dCTP very efficiently and with the lowest Km described so far. Because the biological function of mammalian all-alpha NTP pyrophosphatases remains uncertain, we examined the role of DCTPP1 in the maintenance of pyrimidine nucleotide pools and cellular sensitivity to pyrimidine analogues. DCTPP1-deficient cells accumulate high levels of dCTP and are hypersensitive to exposure to the nucleoside analogs 5-iodo-2´-deoxycytidine and 5-methyl-2´-deoxycytidine. Our data indicate that DCTPP1 has a central role in the balance of dCTP and the metabolism of deoxycytidine analogues, thus contributing to the preservation of genome integrity.
Source: BJ Gene - Category: Biochemistry Authors: Tags: BJ Metabolism Source Type: research