103
at the replication fork. During the SOS induction, pol IV production is increased
10-fold and one of its functions during this time is to interfere with the pol III holoenzyme processivity. This creates a checkpoint, stops replication, and allows time
to repair DNA lesions via the appropriate repair pathway [26]. Another function of
pol IV is to perform translesion synthesis at the stalled replication fork, for example,
bypassing N2-deoxyguanine adducts at a faster rate than transversing undamaged
DNA. Cells lacking dinB gene have a higher rate of mutagenesis caused by DNA
damaging agents [27].
DNA polymerase V (pol V) is a Y-family DNA polymerase that is involved in
SOS response and translesion synthesis DNA repair mechanisms [28]. Transcription of pol V via the umuDC genes is highly regulated to only produce pol V when
damaged DNA is present in the cell, generating the SOS repsonse. Stalled polymerases cause RecA to bind to the ssDNA, which causes the LexA protein to autodigest.
LexA then loses is ability to repress the transcription of the umuDC operon. The
same RecA-ssDNA nucleoprotein post-translationally modifies the umuD protein
into the umuD′ protein. UmuD and umuD′ form a heterodimer that interacts with
umuC, which in turn activates the umuC’s polymerase catalytic activity on the damaged DNA [29].
Pol η, pol ι, and pol κ are family Y DNA polymerases involved in the DNA repair
by translesion synthesis and encoded by genes polH, polI and polK, respectively.
Members of family Y have 5 common motifs to aid in binding the substrate and
primer terminus and they all include the typical right-hand thumb, palm and finger domains, with additional domains like little finger (LF), polymerase-associated
domain (PAD), or wrist. The active site, however, differs between family members
due to the different lesions being repaired [30]. Polymerases in family Y have low
fidelity, but have been proven to do more good than harm as mutations can cause
various diseases, such as skin cancer and xeroderma pigmentosum variant (XPS).
The importance of these polymerases is evidenced by the fact that one refers to the
gene encoding DNA polymerase η as XPV, because the loss of this gene results in
the disease xeroderma pigmentosum variant [30]. Pol η is particularly important
for allowing accurate translesion synthesis of the DNA damage resulting from ultraviolet radiation or UV. The functionality of pol κ is not completely understood,
but researchers have found two probable functions. Pol κ is thought to act as an
extender or an inserter of a specific base at certain DNA lesions. All three translesion synthesis polymerases, along with Rev1, are recruited to damaged lesions via
stalled replicative DNA polymerases. There are two pathways of damage repair
leading researchers to conclude that the chosen pathway depends on which strand
contains the damage, the leading or the lagging strand [30].
4.3 Pol Inhibitors and Possible Mechanisms of Action
All known inhibitors can be subdivided into several groups according to certain
analytical criteria. Mostly, inhibitors are sorted by their chemical nature or by specificity regarding to certain polymerases and polymerase families.
4 DNA Dependent DNA Polymerases as Targets for Low-Weight …
at the replication fork. During the SOS induction, pol IV production is increased
10-fold and one of its functions during this time is to interfere with the pol III holoenzyme processivity. This creates a checkpoint, stops replication, and allows time
to repair DNA lesions via the appropriate repair pathway [26]. Another function of
pol IV is to perform translesion synthesis at the stalled replication fork, for example,
bypassing N2-deoxyguanine adducts at a faster rate than transversing undamaged
DNA. Cells lacking dinB gene have a higher rate of mutagenesis caused by DNA
damaging agents [27].
DNA polymerase V (pol V) is a Y-family DNA polymerase that is involved in
SOS response and translesion synthesis DNA repair mechanisms [28]. Transcription of pol V via the umuDC genes is highly regulated to only produce pol V when
damaged DNA is present in the cell, generating the SOS repsonse. Stalled polymerases cause RecA to bind to the ssDNA, which causes the LexA protein to autodigest.
LexA then loses is ability to repress the transcription of the umuDC operon. The
same RecA-ssDNA nucleoprotein post-translationally modifies the umuD protein
into the umuD′ protein. UmuD and umuD′ form a heterodimer that interacts with
umuC, which in turn activates the umuC’s polymerase catalytic activity on the damaged DNA [29].
Pol η, pol ι, and pol κ are family Y DNA polymerases involved in the DNA repair
by translesion synthesis and encoded by genes polH, polI and polK, respectively.
Members of family Y have 5 common motifs to aid in binding the substrate and
primer terminus and they all include the typical right-hand thumb, palm and finger domains, with additional domains like little finger (LF), polymerase-associated
domain (PAD), or wrist. The active site, however, differs between family members
due to the different lesions being repaired [30]. Polymerases in family Y have low
fidelity, but have been proven to do more good than harm as mutations can cause
various diseases, such as skin cancer and xeroderma pigmentosum variant (XPS).
The importance of these polymerases is evidenced by the fact that one refers to the
gene encoding DNA polymerase η as XPV, because the loss of this gene results in
the disease xeroderma pigmentosum variant [30]. Pol η is particularly important
for allowing accurate translesion synthesis of the DNA damage resulting from ultraviolet radiation or UV. The functionality of pol κ is not completely understood,
but researchers have found two probable functions. Pol κ is thought to act as an
extender or an inserter of a specific base at certain DNA lesions. All three translesion synthesis polymerases, along with Rev1, are recruited to damaged lesions via
stalled replicative DNA polymerases. There are two pathways of damage repair
leading researchers to conclude that the chosen pathway depends on which strand
contains the damage, the leading or the lagging strand [30].
4.3 Pol Inhibitors and Possible Mechanisms of Action
All known inhibitors can be subdivided into several groups according to certain
analytical criteria. Mostly, inhibitors are sorted by their chemical nature or by specificity regarding to certain polymerases and polymerase families.
4 DNA Dependent DNA Polymerases as Targets for Low-Weight …