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Biochem J. 2016 Sep 1;473(17):2635-43. doi: 10.1042/BCJ20160302. Epub 2016 Jun 20.

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine.

Author information

1
Departmento de Bioquímica y Farmacología Molecular, Instituto de Parasitología y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Armilla (Granada), 18016, Spain.
2
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Science, H-1117 Budapest, Hungary.
3
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Science, H-1117 Budapest, Hungary Department of Applied Biotechnology and Food Sciences, University of Technology and Economics, H-1111 Budapest, Hungary.
4
Departmento de Bioquímica y Farmacología Molecular, Instituto de Parasitología y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Armilla (Granada), 18016, Spain dgonzalez@ipb.csic.es avidal@ipb.csic.es.

Abstract

Decitabine (5-aza-2'-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two 'house-cleaning' nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2'-deoxycytidine-5'-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.

KEYWORDS:

DCTPP1; XTP3-TPA; dUTPase; decitabine; nucleotide pool

PMID:
27325794
DOI:
10.1042/BCJ20160302
[Indexed for MEDLINE]

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