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A. Yu. Nyporko
by DNA polymerases during replication is the addition of nucleoside monophosphate deriving from appropriate nucleoside triphosphate to OH-group on 3′-end of
growing DNA chain [1].
Second important DNA polymerases’ function in living systems is participation
in the DNA repair, aimed at correcting errors of the DNA synthesis during replication as well as numerous injuries that occur in DNA as a result of chemical and
physical factors [2]. Most of the reparation process involves removing the damaged
fragment with subsequent single-stranded DNA synthesis that is performed by DNA
polymerases.
Besides their essential tasks in vivo, DNA polymerases are now the key tool in
numerous important molecular biological and medical core technologies, such as
the widely applied polymerase chain reaction (PCR), cDNA cloning, genome sequencing, nucleic acids based diagnostics, and in techniques to analyze the ancient
and otherwise damaged DNA [3].
Like the other cellular and molecular “bottlenecks”, the DNA dependent DNA
polymerases are attractive targets for low-molecular weight inhibitors. These compounds can be used (and are actually used) as molecular tuning tools in molecular
biology investigations, and as antineoplastic and antiviral drugs as well. Despite
numerous investigations, devoted to the search for DNA pol inhibitors and their development, some fundamental problems in this field are still unresolved. The most
important of them is the problem of structural insights of inhibitor–pol interactions
and the inhibitor selectivity to different DNA polymerases. Detailed comprehension
of these insights would not only give a possibility to design new drugs with highly
selective activity with respect to the targeted polymerases, but would essentially
extend our understanding of the structural basis of replicative/reparative processes
as a whole.
4.2 Diversity of DNA Dependent DNA Polymerases
According to present views, all of the known DNA polymerases are divided into
seven families based on their sequence homology (especially, sequences of the
catalytic domain) and the structure of catalytic domain. Six of them—A, B, C,
D, X and Y—are DNA-dependent DNA polymerases, one is a DNA polymerase
of a different nature, namely it is RNA-dependent (more commonly known as
‘reverse transcriptases’ or RT family) [3]. The spectra of DNA polymerases’
families are individual for different organic kingdoms. For example, bacteria
usually contain DNA polymerases of A, B, C, X and Y families, while archaea
have members of families B, D, X and Y. Among eukaryotic DNA polymerases, we can find various members of A, B, X, Y families (and at least one RTmember—telomerase supplying synthesis of the terminal fragment of chromosome which cannot be synthesized in the matrix way). Viral DNA polymerases
are presented by families A, B and X (as well as RT—reverse transcriptases of
retroviruses) (see Table 4.1).
A. Yu. Nyporko
by DNA polymerases during replication is the addition of nucleoside monophosphate deriving from appropriate nucleoside triphosphate to OH-group on 3′-end of
growing DNA chain [1].
Second important DNA polymerases’ function in living systems is participation
in the DNA repair, aimed at correcting errors of the DNA synthesis during replication as well as numerous injuries that occur in DNA as a result of chemical and
physical factors [2]. Most of the reparation process involves removing the damaged
fragment with subsequent single-stranded DNA synthesis that is performed by DNA
polymerases.
Besides their essential tasks in vivo, DNA polymerases are now the key tool in
numerous important molecular biological and medical core technologies, such as
the widely applied polymerase chain reaction (PCR), cDNA cloning, genome sequencing, nucleic acids based diagnostics, and in techniques to analyze the ancient
and otherwise damaged DNA [3].
Like the other cellular and molecular “bottlenecks”, the DNA dependent DNA
polymerases are attractive targets for low-molecular weight inhibitors. These compounds can be used (and are actually used) as molecular tuning tools in molecular
biology investigations, and as antineoplastic and antiviral drugs as well. Despite
numerous investigations, devoted to the search for DNA pol inhibitors and their development, some fundamental problems in this field are still unresolved. The most
important of them is the problem of structural insights of inhibitor–pol interactions
and the inhibitor selectivity to different DNA polymerases. Detailed comprehension
of these insights would not only give a possibility to design new drugs with highly
selective activity with respect to the targeted polymerases, but would essentially
extend our understanding of the structural basis of replicative/reparative processes
as a whole.
4.2 Diversity of DNA Dependent DNA Polymerases
According to present views, all of the known DNA polymerases are divided into
seven families based on their sequence homology (especially, sequences of the
catalytic domain) and the structure of catalytic domain. Six of them—A, B, C,
D, X and Y—are DNA-dependent DNA polymerases, one is a DNA polymerase
of a different nature, namely it is RNA-dependent (more commonly known as
‘reverse transcriptases’ or RT family) [3]. The spectra of DNA polymerases’
families are individual for different organic kingdoms. For example, bacteria
usually contain DNA polymerases of A, B, C, X and Y families, while archaea
have members of families B, D, X and Y. Among eukaryotic DNA polymerases, we can find various members of A, B, X, Y families (and at least one RTmember—telomerase supplying synthesis of the terminal fragment of chromosome which cannot be synthesized in the matrix way). Viral DNA polymerases
are presented by families A, B and X (as well as RT—reverse transcriptases of
retroviruses) (see Table 4.1).