期刊
BIOCHEMICAL JOURNAL
卷 459, 期 -, 页码 171-180出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20130894
关键词
dCTP pyrophosphatase 1 (DCTPP1); nucleotide analogue; nucleotide metabolism; 5-formyl-dCTP; nucleoside triphosphate pyrophosphatase (NTP pyrophosphatase); XTP3-transactivated protein A (XTP3-TPA)
资金
- Junta de Andalucia [BIO-199, P06-CVI-02165]
- Ministerio de Economia y Competitividad (Plan Nacional de Investigacion) [SAF2010-20059, SAF2011-27860]
- Red de Investigacion Cooperativa en Enfermedades Tropicales (RICET) FIS (Fondo de Investigaciones Sanitarias) Network [RD06/0021]
The size and composition of dNTP (deoxyribonucleoside triphosphate) 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 such mechanism involves catabolic activities that convert deoxynucleoside triphosphates into their monophosphate form. Human cells possess an all-alpha NTP (nucleoside triphosphate) pyrophosphatase named DCTPP1 [dCTP pyrophosphatase 1; also known as XTP3-TPA (XTP3-transactivated protein A)]. In the present study, 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 hydrolyses 5-formyl-dCTP very efficiently and with the lowest K-m value 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 analogues 5-iodo-2'-deoxycytidine and 5-methyl-2'-deoxycytidine. The results of the present study 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.
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