Authors

Discussion

Agents modulating synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics.  Processes such as DNA replication and DNA repair depend on the accurate regulation of the synthesis and degradation of nucleotides. In humans, the main dNTPase is SAMHD1, which controls the homeostatic balance of dNTP pools. TbHD82 is a SAMHD1 ortholog identified in Trypanosoma brucei and sequence alignments show that the amino acids involved in substrate binding and catalysis are all conserved. While TbHD82 is not essential in vitro for proliferation of procyclic and bloodstream form parasites, its absence induces an accumulation of dATP, dCTP and dTTP, suggesting that the protein is a dNTPase. The expression of TbHD82 is cell cycle-dependent and HD82-deficient parasites exhibit a hypermutator phenotype, defects in cell cycle progression with a shortened S-phase and increased fork speed and instability. In addition, TbHD82 null mutants exhibit enhanced activation of the DNA damage response and the enzyme is up-regulated upon genotoxic insult. All these features are in line with the consequences of dNTP imbalances. We suggest that TbHD82 contributes to the maintenance of genome integrity and replication stability by modulating the excessive or unbalanced accumulation of dNTPs.