From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
DNA is constantly subjected to injuries
inflicted by external agents such as UV light or cigarette smoke, by
intracellular by-products of metabolism such as reactive oxygen
species, or by spontaneous decay. DNA lesions interfere with
replication and with transcription and if left in DNA can cause
mutation, malfunction, and cell death. These deleterious effects are
usually prevented by DNA repair mechanisms, which remove the damaged
nucleotide and restore the original DNA sequence (for review, see Ref.
1). However, the repair mechanisms are not fully efficient, and some lesions persist in the DNA. The attempt to replicate such unrepaired lesions usually leads to an interruption of replication and to the
formation of a ssDNA1 region
carrying the damaged nucleotide, a gap-lesion structure.
Filling in of gap-lesion structures can be done by one of two known
mechanisms: recombinational repair and translesion replication. Recombinational repair consists of patching the gap with a DNA segment
that was cut out from the undamaged strand in the fully replicated
sister chromatid (2, 3). This converts the damaged region into the
dsDNA form, enabling a second attempt of error-free repair.
Alternatively, the gap may be filled in by DNA synthesis, a process
that is inherently mutagenic because of the miscoding nature of most
damaged nucleotides. This pathway was, therefore, termed translesion
replication (TLR2),
translesion synthesis, error-prone repair, mutagenic repair, bypass
synthesis, or lesion bypass (4-6). A third mechanism that may exist
was termed copy choice replication, but only little is known about it
(7-9). In the last 2 years a major breakthrough has occurred with the
discovery that TLR is carried out by specialized DNA polymerases that
belong to a novel superfamily. These DNA polymerases, which were found
in a number of organisms ranging from Escherichia coli to
humans, exhibit a high frequency of errors during in vitro
DNA synthesis. Some of them clearly function in TLR, whereas the
functions of others are unknown yet (for recent reviews, see Refs.
10-14). This review will present an overview of the new DNA
polymerases, focus on E. coli DNA polymerase V and human DNA
polymerase In E. coli TLR is regulated by the SOS response. The
main component of this reaction is one of the novel DNA
polymerases, a product of the umuC gene termed pol V
(15, 16).3 The
umuC gene is a typical SOS gene, which is repressed by LexA and induced by RecA (for a review on the SOS system see Ref. 1). The
lesion bypass activity of pol V requires three additional proteins:
UmuD', a shorter form of UmuD formed by RecA-mediated proteolysis (17),
RecA, and SSB (15, 16). In addition, it is stimulated by the
processivity subunits of pol III, namely the E. coli contains another member of the new DNA polymerase
family, pol IV, the product of the dinB gene. pol IV is a
low fidelity DNA polymerase (18), which is responsible for a special
branch of mutagenesis observed in unirradiated phage Remarkably, homologs of umuC are carried on natural
conjugative plasmids present in bacteria (25). These plasmids often carry multiple antibiotic resistance genes and are responsible, in
part, for the growing problem of resistance toward antibiotics among
bacterial pathogens (26). One of these homologs, mucB, is
present in plasmid R46 and in its derivative pKM101, which is used to
increase the sensitivity of the Salmonella Ames test for
mutagens (27). MucB was shown to be pol RI, a DNA polymerase specialized for lesion bypass (28). Like pol V, the bypass activity of
pol RI requires also the plasmid-encoded MucA' protein (homolog of
UmuD') and the host RecA and SSB proteins. An intriguing possibility is
that these mutation-producing (mutase) polymerases have a role in the
phenomenon of antibiotics resistance among bacterial pathogens (28).
The yeast Saccharomyces cerevisiae contains two TLR systems:
the pol Human cells contain TLR systems similar to the S. cerevisiae
pol Similar to S. cerevisiae, humans contain a TLR system based
on pol Humans contain two additional homologs of umuC:
hRAD30B, encoding DNA polymerase Two additional new DNA polymerases were discovered recently in humans,
pol µ and pol E. coli TLR was reconstituted with purified components
first by the late H. Echols and his co-workers (58), and more
recently in the laboratories of Livneh (59) and Goodman (60). Soon thereafter it was found that the actual translesion replication step
occurs in the absence of pol III holoenzyme and that UmuC is a DNA
polymerase, termed pol V (15, 16). pol V by itself is an extremely weak
DNA polymerase and is unable to bypass lesions. It has a low
processivity (~6) and no exonucleolytic proofreading (15, 16).
pol V is greatly activated and acquires the ability to bypass lesions
upon addition of three additional proteins: UmuD', RecA, and SSB. Under
these conditions pol V replicates effectively abasic sites (15, 16) and
two major UV photoproducts, a thymine-thymine CPD and a
thymine-thymine 6-4 adduct (61). Lesion bypass by pol V has a
lesion-dependent specificity; mostly dAMP is inserted
opposite an abasic site; two As are inserted opposite a thymine-thymine
CPD and GA is inserted opposite a thymine-thymine 6-4 adduct (16,
61).
Replication of undamaged DNA by pol V is mutagenic (61, 62), producing
point mutations at an average frequency of 1.3 × 10 The TLR system based on pol V is, so far, the only multiprotein system
reconstituted from purified components. Based on the current data, the
following model can be drawn for TLR by pol V (Fig.
1). As the replication fork encounters an
unrepaired lesion in the DNA, replication stops. At this stage the
single-stranded region is bound by SSB, the single strand-binding
protein. The major function of this protein is to dissolve secondary
structures in DNA, such that the DNA can be easily replicated. SSB is a
homotetramer, and the bound ssDNA is wrapped around the protein (65).
Once replication stops, however, the binding of ssDNA around SSB
exposes it to injuries. At this stage the RecA protein displaces SSB, forming a protective helical nucleoprotein filament around the DNA.
This protein filament protects the DNA from degradation, as was shown
both in vivo and in vitro (3). In addition, the RecA-DNA filament promotes the cleavage of LexA, the global repressor of the SOS regulon. This in turn leads to induction of the SOS response, including transcriptional activation of genes involved in
error-free excision repair and in the tolerance of DNA damage (e.g. recA, umuD, and umuC) (1). In
addition to its protective and regulatory functions, RecA is also
directly involved in the two major tolerance mechanisms; it is the
major recombinase in recombinational repair, and it is directly
required for TLR. These multiple repair functions of RecA warrant the
title "guardian of the bacterial genome."
INTRODUCTION
TOP
INTRODUCTION
An Overview of Translesion...
The SOS Paradigm: Translesion...
Error-free Translesion...
The Function of TLR...
Is TLR a Major...
REFERENCES
, and conclude with a discussion of some general issues
in TLR.
An Overview of Translesion Replication Systems
TOP
INTRODUCTION
An Overview of Translesion...
The SOS Paradigm: Translesion...
Error-free Translesion...
The Function of TLR...
Is TLR a Major...
REFERENCES
subunit sliding clamp
and the
complex clamp loader (15). Based on genetic evidence pol V
is the main lesion bypass polymerase in E. coli.
Inactivating TLR by a umuC mutation leads to a modest reduction in resistance to DNA-damaging agents such as UV light, suggesting that TLR has a small contribution to survival or DNA repair.
On the other hand, the umuC mutation strongly decreases mutagenesis by DNA-damaging agents, implying that most of the mutations
are caused by pol V-dependent TLR (1, 17).
when it
infects an irradiated E. coli host (19). Acting in this
pathway or when overproduced in E. coli cells, pol IV leads
to the preferential production of frameshift mutations (20-22). It was
suggested that pol IV can perform lesion bypass in vivo, at
least in specific cases (23), and that it is involved in spontaneous
mutagenesis (24); however, its full biological role is not clear.
(REV) system and the pol
(RAD30)
system. The REV system contains three genes:
REV1, REV3, and REV7 (29).
REV3 encodes the DNA polymerase subunit, which together with
REV7 forms pol
(30). Interestingly, pol
, is similar
to the "classical" pol
rather than to UmuC. In
vitro, pol
was shown to bypass a thymine-thymine cyclobutyl
pyrimidine dimer (CPD), although with moderate efficiency (30). In
addition, pol
was shown to extend mismatches with high efficiency,
including nucleotides inserted opposite a lesion (31). REV1 is similar
to the E. coli UmuC; however, it has dCMP transferase
activity rather than DNA polymerase activity (32). Inactivation of the
REV system causes mild or no UV sensitivity, but it greatly
reduces UV mutagenesis, indicating that pol
is important in TLR in
S. cerevisiae (29). In addition, S. cerevisiae
contains an additional homolog of umuC, termed
RAD30. This gene encodes pol
, a DNA polymerase that is specialized for replicating certain lesions. Most remarkably, pol
replicates a thymine-thymine CPD with the same efficiency and the same
accuracy as it replicates a non-damaged thymine-thymine sequence (33).
pol
provides the paradigm for the new phenomenon of non-mutagenic,
relatively error-free bypass of DNA lesions. No homolog of
dinB was found in S. cerevisiae.
and pol
ones and two additional novel DNA polymerases similar to pol
. Humans contain homologs of the yeast
REV3 (34) and REV7 (35) genes and are therefore
likely to have pol
, although this was not yet proven biochemically.
Humans contain also a homolog of REV1, which was reported to
have dCMP transferase activity (36), similar to the yeast enzyme.
In vivo experiments with human cultured cells have shown
that decreasing the expression of REV3 (34) or of
REV1 (37) with antisense RNA led to a reduction in UV
mutagenesis, suggesting a major role for the REV system in
TLR. Interestingly, the attempts to knock-out REV3 in mice led to embryonic lethality, and no cell line could be established from these embryos (38-40). This indicates a vital role for pol
and possibly for TLR in mammals.
. pol
is encoded by the XP-V gene (41, 42),
which is mutated in the variant form of the genetic disease xeroderma pigmentosum (XP; the other forms of the disease are caused by mutations
in error-free nucleotide excision repair). This disease is
characterized by sun sensitivity and cancer predisposition, and cell
lines established from XP-V patients exhibit hypermutability by and sensitivity to UV radiation (1, 43). Thus, although pol
-dependent TLR is not essential in humans, it does act
as a major anti-mutagenic and therefore anti-cancer mechanism. This provides the most convincing example that TLR may be functionally non-mutagenic under certain biologically important circumstances.
(44, 45), and
hDINB1, encoding pol
(termed also pol
)4 (46-48, 52). The
biological functions of these polymerases are unknown yet. pol
is
distinguished by its remarkable violation of the base pairing rules
common to all known DNA polymerases; it prefers to insert dGMP opposite
a template T (31, 44, 45). Surprisingly it was found that pol
has
an associated deoxyribose-phosphate lyase activity, similar to
that of pol
(53). This raises the possibility that pol
is a
polymerase tailored to correct a potential mutagenic T in a template,
e.g. in a T:G mismatch, where the thymine residue was formed
by deamination of 5-methylcytosine (53). pol
has the ability to
bypass some lesions in vitro (47, 48), and like the other
DNA polymerases of its family, it is highly mutagenic on undamaged DNA
(46, 52, 54). However, its biological function is still unknown.
. These polymerases belong to the X family, rather
than the UmuC/DinB family. pol µ is similar to terminal
deoxynucleotidyltransferase. It has a high error frequency in
vitro, and based on its presence at elevated amounts in tissues of
the immune system, it was suggested to be involved in the generation of
somatic mutation in the immunoglobulin genes (55, 56). pol
is a pol
-like DNA polymerase, which seems to be an accurate polymerase. It
might be functioning in error-free repair in meiosis (56, 57).
The SOS Paradigm: Translesion Replication Is Performed by pol
V, an Inducible Specialized DNA Polymerase
TOP
INTRODUCTION
An Overview of Translesion...
The SOS Paradigm: Translesion...
Error-free Translesion...
The Function of TLR...
Is TLR a Major...
REFERENCES
4/nucleotide (62). All types of point mutations
(transitions, transversions, and frameshifts) are increased by pol V,
but it shows a preference for generating transversions at a frequency 74-fold higher than pol III holoenzyme (62). Based on these properties
pol V has been suggested to be responsible for the phenomenon of
untargeted mutagenesis, where mutations are formed under SOS conditions
in undamaged regions of the chromosome (62). Mismatches formed by
untargeted mutagenesis are subjected in vivo to mismatch
repair (63). Interestingly, the mismatch repair system is less
efficient in removing mismatches that lead to transversions (64).
Therefore, pol V tends to produce mutations that can escape mismatch
repair (62).
View larger version (34K):
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Fig. 1.
Model of SOS translesion replication by DNA
polymerase V. The two DNA strands are shown as green
lines, and the replication-blocking lesion is represented by
the red rectangle. The three major steps in TLR
are pre-initiation (2), in which the RecA
nucleoprotein filaments assembles; initiation (3 and 4), which involves binding of pol V to the
primer-template and loading of the subunit clamp; and lesion
bypass by pol V holoenzyme (5). SSB is suggested to
help in displacing RecA from DNA both at the initiation and lesion
bypass steps.
The first step in TLR is the pre-initiation stage, which
involves the assembly of a RecA nucleoprotein filament (Fig. 1, step 2) (66). This filament, which assembles in the 5'3'
direction, covers the ssDNA region and continues to the dsDNA region
adjacent to the ssDNA region, including the primer terminus near the
lesion (66). In the subsequent step of initiation (Fig. 1,
step 3), pol V binds to the primer-template, guided by the
RecA filament, which serves as a targeting platform (66, 67). Loading
of pol V onto the primer-template is stabilized by at least three known
protein-protein and DNA-protein interactions. UmuD' interacts with the
RecA nucleoprotein filament (67); UmuD' interacts with UmuC (68, 69);
and UmuC interacts with the primer-template. No direct interaction was
demonstrated between UmuC and RecA. Initiation of TLR by pol V requires
the local dissociation of RecA monomers from the DNA near the
primer-template to allow proper binding of pol V to the DNA (Fig. 1,
step 3). This suggestion is based on the strong inhibition
of initiation of TLR caused by ATP
S, a poorly hydrolyzable ATP
analog that strongly stabilizes RecA binding to DNA (66). This strong
binding presumably inhibits displacement of RecA from the
primer-template region by pol V. SSB is likely to help pol V in
displacing RecA from DNA (70). It is noteworthy that SSB was shown to
interact with pol RI (MucB) (71).
Once loaded on the DNA, the binding of pol V is further stabilized by
the addition of the processivity subunits of pol III, the subunit
and the
complex (Fig. 1, step 4). These proteins were
shown to increase the processivity of pol V (61), although at this
point it is not known whether they are involved in TLR in
vivo. The pol V holoenzyme assembly commences DNA synthesis, and
when encountering the lesion, it replicates through it (lesion bypass; Fig. 1, step 5). Experimental evidence was
presented for SSB-driven dissociation of RecA during polymerization by
pol V in the presence of ATP
S (70). In that system, based on a long synthetic oligonucleotide template, lesion bypass in the presence of
ATP was extremely low; therefore, the validity of the conclusions for
lesion bypass in the presence of the native cofactor ATP remains to be
determined. In a TLR system based on a gapped plasmid, lesion bypass
was found to be inhibited by ATP
S, consistent with the notion that
progression of pol V causes disassembly of the RecA filament. The
inhibitory effect of ATP
S on bypass by pol V was milder than the
effect on initiation (66). These results suggest that once loaded on
the primer-template at the initiation stage, the binding of pol V to
DNA is strongly stabilized such that it can displace RecA from DNA,
aided by SSB, even in the presence of ATP
S.
How does pol V TLR terminate? Once the lesion is bypassed, pol III
holoenzyme should take over again (Fig. 1, step 6). The mechanism of polymerase switching is not clear. It was previously shown
that RecA filament disassembles in a reaction requiring ATP hydrolysis
(72). This led to the suggestion that bidirectional disassembly of RecA
(70), from the 3' end by the action of pol V and from the 5' end
spontaneously (or SSB-stimulated), leads to dissociation of pol V, such
that pol III can take over.
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Error-free Translesion Replication by DNA Polymerase ![]() |
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The activity of purified human pol was examined on several
types of DNA lesions. It was found that there is a variability in the
bypass capability of pol
. A thymine-thymine 6-4 adduct is
essentially a complete block to pol
; AAF-modified guanine and
8-oxoguanine are bypassed well, whereas an abasic site and a
cisplatin-guanine adduct are bypassed to a lesser but still a
significant extent (73-76). Analysis of the specificity of bypass revealed that pol
inserts AA opposite a thymine-thymine CPD and
primarily C opposite AAF-modified or cisplatin-modified guanines, which
are the correctly inserted nucleotides (73, 74). When replicating
through an abasic site pol
inserts either an A or a G, whereas
8-oxoguanine instructs the insertion of primarily C but also A (73, 76,
77). The practical implication of these results is that replication by
pol
will lead to a relatively accurate bypass. It was reported that
pol
also inserts incorrect nucleotides opposite the lesions, but
those are extended with a much lower efficiency (73). Thus, the
relatively accurate replication is achieved by (a)
preferential insertion of the correct nucleotide and
(b) preferential extension of the correct nucleotide. As
described above, the biological significance of the non-mutagenic bypass of thymine-thymine CPD is evident from the fact that cells lacking pol
are hypermutable by UV light, and XP-V patients show a
high predisposition to sunlight-induced skin cancer (1, 43). Also the
non-mutagenic bypass of 8-oxoguanine seems to be significant in
vivo, at least in yeast. This is based on the observation (76)
that GC
TA mutations (presumably caused by 8-oxoguanine) were
increased in a synergetic manner when the gene coding for pol
was
knocked-out in a yeast strain lacking 8-oxoguanine glycosylase (which
removes 8-oxoguanine from DNA). The action of pol
in this case may
be part of the repair of 8-oxoguanine-adenine mispairs by the mismatch
repair system (78).
Determination of the accuracy of replication by pol on undamaged
DNA revealed that it is highly error-prone. In one study misinsertion
was estimated to be one in 100-1000 nucleotides polymerized (79) and
one in 18-380 nucleotides in another (80). Most interestingly, the
replication of an undamaged thymine-thymine sequence and a thymine-thymine CPD occurred with the same efficiency and the same
error frequency of 1% (79). This error frequency is highly mutagenic
when compared with the error frequency of a replicative polymerase
opposite an undamaged template T (e.g. 10
6).
However, when there is a lesion in DNA and coding information is
compromised, the chances of misincorporation may be close to 100%.
Compared with this, an error frequency of 1% is 1-2 orders of
magnitude more accurate, making pol
functionally accurate in
bypassing the thymine-thymine CPD.
How can pol replicate lesions as diverse as a thymine-thymine CPD,
cisplatin-guanine adducts, and AAF-guanine adducts with such accuracy?
The common denominator of these lesions is that the regions involved in
base pairing are not directly affected by the chemical modification. It
is possible that pol
can identify these non-modified regions and
extract base pairing information. Having possibly a flexible active
site might allow, or even stabilize, an interaction of the modified
template base with an incoming nucleotide. This would predict that
non-mutagenic bypass by pol
will be generally limited to base
modifications that do not involve the base pairing atoms.
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The Function of TLR in Microorganisms: DNA Repair or Promoting Genetic Variability? |
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In E. coli and in S. cerevisiae,
inactivation of translesion replication causes a strong reduction in
mutagenesis by agents such as UV radiation but only a slight decrease
in the resistance (1). This led to two opposing views on the function
of TLR: 1) that it is a minor repair process, which increases survival at the expense of increased mutagenesis; and 2) that it acts as mutator
to increase the adaptation to the environment of a population of
microorganisms under genotoxic stress (81-83). The fact that pol V is
a mutator polymerase on undamaged DNA and that it forms preferentially
transversions is consistent with the latter (62), because these types
of mutations are repaired by mismatch repair least effectively (64). It
is possible that TLR has evolved initially as a DNA repair mechanism to
increase survival in response to genotoxic agents. This is consistent
with the higher survival conferred by plasmid-born umuC
homologs (25). This would be a generic, even primitive DNA repair, in
which the lesion is not removed but rather read-through. Then, as more
sophisticated repair mechanisms evolved, the importance of TLR for
repair decreased, but it was preserved due to its mutator phenotype.
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Is TLR a Major Tolerance Mechanism in Mammals? |
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The argument that mutagenesis facilitates adaptation is reasonable
for unicellular organisms. However, for multicellular organisms, this
argument faces the problem that the enhancement of mutation rates may
eventually facilitate the formation of cancer, which might kill the
organism. Although the role of recombinational mechanisms in DNA
damage tolerance in mammals is not fully clear, it seems that
recombination is low in somatic cells (84, 85). In contrast,
experiments with vectors carrying site-specific lesions have clearly
shown that lesions are bypassed in mammalian cells (e.g.
Refs. 86 and 87). Moreover, as discussed above multiple DNA
polymerases with either a proven or suspected role in lesion bypass exist in mammals. These findings argue that lesion bypass is a
major pathway of tolerating DNA lesions, more important than recombination. How then are the mutagenic consequences of the bypass
dealt with? One unexpected answer came from the finding that at least
some lesions, which are frequently formed in DNA, can be bypassed with
a relatively high accuracy, e.g. thymine-thymine CPD by pol
. Another argument would be that the vast majority of the mammalian
genome is composed of non-coding DNA, and therefore point mutations
would not necessarily have adverse effects on the cell. This non-coding
DNA contains many repetitive sequences, which may explain also why
mechanisms based on homologous recombination would be strongly
suppressed; having an extensive recombinational repair mechanism runs
the risk of gross rearrangements, a risk that is more significant than
that of point mutations.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This work was supported by United States-Israel Binational Science Foundation Grant 1999141, Israel Science Foundation Grant 78/00, and by a grant from The Minerva Foundation, Germany.
To whom correspondence should be addressed. Fax: 972-8-9344169;
E-mail: zvi.livneh@weizmann.ac.il.
Published, JBC Papers in Press, May 22, 2001, DOI 10.1074/jbc.R100019200
2 We prefer the term translesion replication over translesion synthesis because the former clearly implies a DNA reaction.
3 We term the umuC gene product pol V, whereas Goodman and colleagues (15) term the complex of UmuD'2C pol V. Until the role of UmuD' is clearly defined, we prefer to call UmuC pol V.
4
The multiplicity of new DNA polymerases and
their discovery within a short period of time caused a confusion in
nomenclature. The protein encoded by hDINB1 was termed pol by one
group (46) and pol
by others (47-49). The name pol
was
previously assigned to a putative polymerase involved in cross-link
repair (50). The name pol
was given also to a yeast polymerase
involved in sister chromatid cohesion (51). This nomenclature problem
will hopefully be resolved in the near future (P. Burgers, manuscript in preparation).
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ABBREVIATIONS |
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The abbreviations used are:
ssDNA, single-stranded DNA;
dsDNA, double-stranded DNA;
TLR, translesion
replication;
pol, polymerase;
CPD, cyclobutyl pyrimidine dimer;
ATPS, adenosine 5'-3-O-
(thio)triphosphate.
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