Although mammalian deoxyribonucleases were discovered more than 60 years ago, interest in these enzymes is not weakening. During the last decade, intensive studies of human DNases culminated in discovery of several novel enzymes exhibiting DNase activity. These include an unusual DNase, lactoferrin. For some enzymes, their three-dimensional structure and molecular mechanisms underlying their functioning have been elucidated. In patients with some autoimmune and viral diseases, catalytic antibodies also contribute to alternative pathways of DNA hydrolysis. Some enzymes exhibiting DNase activity play an important role in pathogenesis of various diseases and also in programmed cell death (apoptosis). This review highlights recent achievement in human deoxyribonuclease research. It also considers mechanisms of DNA hydrolysis. The review also summarizes modern data on the biological role of these enzymes in functioning of the human organism, realization of its protective mechanisms, and possible applications of DNases in medicine.

Pt(2+)-containing derivatives of oligodeoxyribonucleotides were used to evaluate the ligand affinity to the template sites of Klenow fragment of DNA polymerase I from E. coli and DNA polymerase alpha from human placenta. The values of Kd and Gibb's energy (delta G degree) for the complexes of oligodeoxyribonucleotides and their derivatives with the template sites of these enzymes were determined from the effects protecting the enzyme from inactivation by Pt(2+)-containing oligonucleotides. Kd and delta G degree values of the complexes made by DNA polymerases and orthophosphate, triethylphosphate, d(pC)n, d(pT)n, d(pG)n, d(pA)n (where n = 1-25), heterooligonucleotides of various length and structure, and oligothymidylates with partially and completely ethylated internucleotide phosphates were evaluated. The obtained data enabled us to suggest 19-20 mononucleotide units of the template to interact with the protein. Only one template internucleotide phosphate forms a Me(2+)-dependent electrostatic contact (delta G = -1.1...-1.7 kcal/mol) and a hydrogen bond (delta G = -4.4...-4.9 kcal/mol) with the enzyme. It is likely that the mononucleoside units of the template form hydrophobic contacts with the enzymes. The efficiency of such interaction changes with the hydrophobicity of the bases: C less than T less than G approximately A. For both homo- and heterooligonucleotides the contributions of nucleoside units to the affinity of the templates to the enzymes is due to the complementary interactions with the primers. A hypothetical model for the template-primer interaction with DNA polymerases is suggested.

In the interaction between HIV-1 RT and tRNA Lys3 each subunit of the heterodimer interacts with tRNA showing a different affinity: Kd (p66) = 23 nM, Kd (pS1) = 140 nM. Preincubation of heterodimeric RT with tRNA, at concentrations similar to that of the Kd value for p51, leads to an increase of the catalytic activity on poly(A)-oligo(dT). These results were compared to those using different tRNA analogs: oxidized tRNA, tRNAs lacking one, two or three nucleotides from the 3'-end, or ribo-and deoxyribonucleotides mimicking the anticodon loop sequence. In all cases, tRNA analogs were weaker activators of HIV-1 liT than natural tRNA. A possible mechanism of RT p661p51 activation by tRNA and its analogs, mediated through the p5I subunit, is discussed.