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`The GO system protects organisms from the
`mutagenic effect of the spontaneous lesion
`8-hydroxyguanine (7,8-dihydro-8-oxoguanine).
`M L Michaels and J H Miller
`1992, 174(20):6321.
`J. Bacteriol. 
`  
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`JOURNAL OF BACrERIOLOGY, OCt. 1992, p. 6321-6325
`0021-9193/92/206321-05$02.00/0
`Copyright © 1992, American Society for Microbiology
`
`Vol. 174, No. 20
`
`MINIREVIEW
`
`The GO System Protects Organisms from the Mutagenic
`Effect of the Spontaneous Lesion
`8-Hydroxyguanine (7,8-Dihydro-8-Oxoguanine)
`MARK LEO MICHAELS AND JEFFREY H. MILLER*
`Department of Microbiology and Molecular Genetics and the Molecular Biology Institute,
`University of California, Los Angeles, California 90024
`
`INTRODUCTION
`
`The GO system is an error avoidance pathway devoted to
`enhancing the fidelity of DNA replication (31, 35). Although
`the system has been most fully characterized for Eschenchia
`coli, evidence already exists for similar repair proteins in
`other prokaryotes (23, 27) and in higher eukaryotes (29,
`52). The GO system in E. coli is composed of at least
`three proteins, MutM, MutT, and MutY. These three
`proteins are responsible for removing an oxidatively dam-
`aged form of guanine from DNA and the nucleotide pool
`and for the correction of error-prone translesion synthe-
`sis. The damaged form of guanine is 7,8-dihydro-8-oxogua-
`nine (also known as 8-hydroxyguanine or a GO lesion [Fig.
`1A]).
`Despite the fact that the GO system appears to be devoted
`to the prevention of errors emanating solely from the GO
`lesion, it is one of the more important fidelity-enhancing
`systems characterized to date, as judged by the mutation
`rates of strains lacking common error avoidance mecha-
`nisms (31). A knockout of the GO system results in mutation
`rates that are of the same order of magnitude as those in
`mutants lacking the polymerase III proofreading subunit
`(mutD) and about an order of magnitude higher than those in
`mutants lacking the methyl-directed mismatch repair system
`(dam, mutHLS) (31, 32).
`The high mutation rate observed in a GO system knockout
`is attributable in large part to the abundance and miscoding
`potential of the GO lesion. The GO lesion is one of the most
`stable products of oxidative damage to DNA (17). Ionizing
`radiation and other treatments that generate active oxygen
`species produce GO lesions (17). However, such treatments
`are not required in order to generate GO lesions in the cell.
`Mutator strains grown aerobically or anaerobically have
`equal mutation rates (32), suggesting that endogenous pro-
`cesses, such as electron transport or lipid peroxidation, can
`produce the active oxygen species that lead to GO lesions.
`Steady-state levels of this adduct have been estimated to be
`104 per cell in humans and 105 per cell in rodents (20). In
`addition to its high abundance, the GO lesion has miscoding
`potential. The miscoding potential of the lesion might seem
`surprising given the adduct's benign appearance-a nondis-
`torting lesion that is situated outside the base-pairing region
`(40). However, it forms a stable base pair with A, where A is
`
`* Corresponding author.
`
`anti and the GO lesion is syn (24). Rotation of the GO lesion
`to the syn conformation is favored because it relieves steric
`interactions between the C-8 keto group and the sugar ring
`(40).
`Oxidative stress has been implicated as an important
`causative agent of mutagenesis, carcinogenesis, aging, and a
`number of diseases (for reviews see references 19 and 41). In
`this minireview we present recent developments that char-
`acterize the roles of the MutM, MutT, and MutY proteins in
`the GO system, which is responsible for handling one
`specific form of oxidative damage. For reviews of other
`DNA repair systems devoted to oxidative damage, see
`references 18, 19, 22, and 41.
`
`MutM
`
`MutM removes GO lesions from chromosomal DNA. The
`mutM gene is a mutator that specifically increases the rate of
`G. C -> T. A transversions when the gene is disrupted (11).
`It maps to 81 min on the E. coli chromosome (11). Cloning
`and sequencing of the mutM gene revealed that it was
`identical to the f7g gene from E. coli (33).
`The FPG protein was originally characterized as a glyco-
`sylase active on formamidopyrimidine adducts that result
`from the opening of the imidazole ring of guanine (13).
`Subsequent work has shown that the glycosylase is active
`on a variety of modified ring-opened purines (9, 12, 14) and
`that the enzyme also has apurinic/apyrimidinic (AP) endo-
`nuclease (6, 39) and 5'-terminal deoxyribose phosphatase
`(21) activities. The AP endonuclease reaction proceeds
`via a 1-elimination reaction, resulting in a gap limited at
`the 3' and 5' ends by phosphoryl groups (6, 39). Other
`enzymes subsequently excise the resulting 3' end and repair
`the gap.
`The elevated rate of G. C -- T. A transversions in a
`mutM strain cannot be attributed to the loss of an enzyme
`that removes ring-opened purines. While these adducts are
`known to block DNA replication and could lead to cell death
`(10), they are not specific for induction of G. C -- T. A
`transversions. Therefore, it was suspected that MutM might
`also act on a different substrate that could be mutagenic.
`A protein called 8-oxoguanine DNA glycosylase was
`isolated from E. coli on the basis of its ability to remove GO
`lesions from DNA (46). This enzyme turned out to be
`identical to MutM (FPG protein). In vivo DNA replication
`studies using templates modified with GO lesions have
`
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`6322
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`MINIREVIEW
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`J. BACTERIOL.
`
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`FIG. 1. The GO system. (A) 7,8-Dihydro-8-oxoguanine (8-hydroxyguanine). This is the structure of the predominant tautomeric form of
`the GO lesion. (B) Oxidative damage can lead to GO lesions in DNA. The GO lesions can be removed by MutM protein, and subsequent repair
`can restore the original G- C base pair. If the GO lesion is not removed before replication, translesion synthesis can be accurate, leading to
`a C/GO pair, which is a substrate for MutM protein. However, translesion synthesis by replicative DNA polymerases is frequently inaccurate,
`leading to the misincorporation of A opposite the GO lesion. MutY removes the misincorporated adenine from the A/GO mispairs that result
`from error-prone replication past the GO lesion. Repair polymerases are much less error prone during translesion synthesis and can lead to
`a C/GO pair-a substrate for MutM. (C) Oxidative damage can also lead to 8-oxo-dGTP. MutT is active on 8-oxo-dGTP and hydrolyzes it to
`8-oxo-dGMP, effectively removing the triphosphate from the deoxynucleotide pool. If MutT were not active and replication occurred with
`8-oxo-dGTP in the deoxynucleotide pool, replication would be largely accurate because the polymerase preferentially inserts the correct T
`opposite A residues. However, inaccurate replication could result in the misincorporation of 8-oxo-dGTP opposite template A residues,
`leading to A/GO mispairs. MutY could be involved in the mutation process because it is active on the A/GO substrate and would remove the
`template A, leading to the A * T- C- G transversions that are characteristic of a mutT strain. The 8-oxo-dGTP could also be incorporated
`opposite template cytosines, resulting in a damaged C/GO pair that could be corrected by MutM.
`
`shown that polymerases can specifically misincorporate an
`A opposite the GO adduct (37, 50). In these studies, trans-
`formation of E. coli with either single-stranded phage DNA
`or double-stranded plasmid DNA, each containing site-
`specific GO lesions, resulted in a specific G. C -- T. A
`transversion at the site of the adduct. A site-specific GO
`lesion in a single-stranded shuttle vector transformed into
`mammalian cells gave the same results (36). Further, in vitro
`replication studies using eukaryotic polymerase a, 13, or 8 or
`E. coli polymerase I (Klenow fragment) showed that all the
`polymerases tested could specifically misincorporate an A
`opposite the GO adduct (44). Interestingly, replicative DNA
`polymerases were much more error prone than the repair
`polymerases tested (44). The specificity of misincorporation
`of A opposite GO adducts could account for the specific
`increase in G- C -- T. A transversions in a mutM strain.
`Thus, MutM can remove both the cell-killing ring-opened
`purine lesions and the mutagenic GO adducts. Both ring-
`
`opened purines and GO lesions can be generated by oxida-
`tive damage to DNA (9).
`
`MutY
`MutY corrects error-prone DNA synthesis past GO lesions.
`Like a knockout of mutM, a knockout of the mutY gene
`leads to a specific increase in G. C -- T. A transversions
`(38). The mutY gene maps to 64 min on the E. coli chromo-
`some (38). By use of an in vivo recombination system (30),
`the mutY gene was cloned and sequenced (34). It encodes a
`350-amino-acid protein with a mass of 39 kDa. A gene called
`micA with the same phenotype as mutY was subsequently
`identified (42). Sequencing of the micA clone proved that the
`two genes were identical (48).
`Work on the correction of mismatches in heteroduplex
`DNA hinted at a potential role for MutY in A/G mispair
`correction (25, 45). These studies showed that A/G mispairs
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`VOL. 174, 1992
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`MINIREVIEW
`
`6323
`
`could be corrected to C. G base pairs by a mechanism
`independent of DNA methylation and the mismatch repair
`system. Subsequent studies showed that MutY was respon-
`sible for the A/G mispair correction (3). While initial exper-
`iments using partially purified extracts suggested that MutY
`removes a small tract of DNA containing the mispaired A
`residue (26), subsequent purification of the enzyme showed
`that MutY is a glycosylase that removes the mispaired A
`from an A/G mismatch in heteroduplex DNA (4) and that the
`enzyme may also have an associated AP endonuclease
`activity (49).
`Because mutM and mutY strains specifically stimulate
`G. C -- T- A transversions, the genes were suspected to be
`involved in a common repair pathway. MutY is active on an
`A/GO mispair, a substrate that mimics the product of error-
`prone synthesis past a GO lesion (31). MutY removes the
`undamaged A from this damaged mispair. Protection assays
`and gel shift analysis showed that MutY remains bound to
`the DNA after removal of the A (35). This positioning not
`only protects the GO adduct from attack by the MutM
`protein, preventing the loss of one base of information and a
`double strand break, but may also serve as a signal to other
`repair proteins that can complete the repair process (35).
`In addition to the biochemical evidence mentioned above,
`there is strong genetic evidence linking mutM with mutY in
`the GO system. They have nearly identical mutation spectra
`in the lacI forward mutation system, and both stimulate
`specifically G- C -* T. A transversions (11, 38). Further,
`overexpression of MutM from a plasmid can completely
`complement a mutY strain (31). Similarly, a chromosomal
`suppressor of mutY, called Supl7, has been isolated. Supl7
`overproduces the MutM protein by about 15-fold (31). Be-
`cause overexpression of the MutM protein would have no
`effect on the repair of undamaged A/G mispairs, these
`complementation results strongly suggest that although
`MutY is active on both the A/G and A/GO mispair substrates
`in vitro, the major substrate in vivo must be the A/GO
`mispair. Finally, the mutM mutY double mutant has a G- C
`-- T. A transversion rate that is 20-fold higher than the sum
`of the mutation rates of the mutators alone (31). This
`dramatic increase in mutation rate can best be explained by
`the model shown in Fig. 1B, in which MutM and MutY
`prevent mutations by chromosomal GO lesions in an inter-
`dependent manner. If both of the proteins are inactivated,
`the cell's defenses against the mutagenic lesion in DNA are
`largely compromised.
`
`MutT
`MutT removes oxidatively damaged dGTP from the nucle-
`otide pool. The mutT mutator gene (47) maps to about 2.5
`min on the E. coli chromosome (5). Inactivation of the gene
`leads to a specific increase in A. T -- C. G transversions
`indicate that DNA
`(51). Experiments with bacteriophage
`replication is required for expression of the mutT phenotype
`(15). In vitro replication studies with M13 DNA show that
`the A. T -* C. G transversions in a mutT strain are medi-
`ated by A/G, rather that C/T, mispairs (43).
`The mutT gene encodes a 129-amino-acid protein with a
`mass of 15 kDa (1). The MutT protein has a weak dGTPase
`activity (8), and it was proposed that MutT might be active
`on a particular conformation of dGTP, possibly the syn
`conformation (2, 7). This hypothesis would require that
`MutT function directly with the replication machinery, for
`its reaction rate is much slower than syn-anti rotation and
`therefore its presence would not significantly alter the dGTP
`
`synldGTPanti ratio in the cytosol. However, labeled MutT
`protein shows no interaction or association with other E. coli
`proteins, including those known to be involved in DNA
`replication (8).
`(8-oxo-dGTP)
`7,8-dihydro-8-oxo-dGTP
`has
`Recently,
`been identified as a substrate for MutT (28). MutT is three
`orders of magnitude more active on 8-oxo-dGTP than on
`dGTP (28). It degrades 8-oxo-dGTP to 8-oxo-dGMP, thus
`eliminating 8-oxo-GTP as a substrate for DNA synthesis.
`The 8-oxo-dGTP nucleotide is a potent mutagenic substrate
`for DNA replication. E. coli DNA polymerase a inserts
`8-oxo-dGTP with equal efficiency opposite C or A in tem-
`plate DNA and with about 3 to 4% efficiency relative to the
`natural substrates (dGTP and dTTP, respectively) (28).
`The evidence suggests that 8-oxo-dGTP is the biologically
`relevant substrate leading to the mutator phenotype of a
`mutT strain. Misincorporation of 8-oxo-dGTP specifically
`occurring opposite template adenines would lead to A/GO
`mispairs. Subsequent replication would result in an A. T --
`C. G transversion-the characteristic phenotype of a mutT
`strain. The model agrees with the finding that A. T -> C. G
`transversions in a mutT strain involve some form of an A/G,
`rather than a C/T, mispair (43). The model also confirms
`other established data regarding mutT: replication is re-
`quired for observation of the mutT phenotype (15); MutT
`does not associate with other proteins, including the repli-
`cation complex (8); and MutT is not involved in postrepli-
`cation repair or recombination (16).
`
`CONCLUSION
`The error avoidance pathway that has evolved to prevent
`the GO lesion from causing mutations in the E. coli chromo-
`some is elaborate (Fig. 1). The cell faces two distinctly
`different problems relating to GO adducts. One problem is
`the miscoding potential of GO lesions in chromosomal DNA.
`The other problem is the potential for misincorporation of
`8-oxo-dGTP into DNA. Mutation rates are minimized by
`having multiple lines of defense to protect the cell from the
`deleterious effects of GO lesions.
`In the case of chromosomal GO lesions, the cell relies on
`MutM and MutY to prevent G. C -) T. A transversions (31,
`35). MutM removes GO lesions from chromosomal DNA
`(46). If MutM fails to remove all of the GO adducts before
`DNA replication, translesion synthesis can be inaccurate,
`leading to the misincorporation of A opposite the GO adduct
`(44). In vitro studies using purified MutM have shown that
`while MutM is less active on the A/GO substrate than on
`C. GO, it can remove the GO lesion from either heterodu-
`plex (35, 46). Removal of the GO from the A/GO mispair by
`MutM would lead to a G. C -) T. A transversion. How-
`ever, if MutY is present in the reaction mixture, it has a
`higher affinity for the A/GO mispair and removes the misin-
`corporated A (35). MutY remains bound to the site after the
`reaction, preventing MutM from attacking the GO lesion
`opposite the AP site (35). If MutM were to act on the AP/GO
`site, it would lead to the loss of one base of information and
`a double strand break. The bound MutY may also serve as a
`signal to other proteins that can advance the DNA repair
`process (35).
`The other problem that confronts the cell is the misincor-
`poration of 8-oxo-dGTP into DNA. Again, the cell relies on
`two systems to prevent errors due to this mutagenic sub-
`strate. First, MutT protein hydrolyzes 8-oxo-dGTP to 8-oxo-
`dGMP (28). This virtually eliminates the triphosphate from
`the nucleotide pool and helps to prevent its misincorporation
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`6324
`
`MINIREVIEW
`
`J. BACTERIOL.
`
`opposite template adenines. The second defense occurs
`during the DNA polymerization step, in which nucleotide
`selection and/or editing by the DNA polymerase provides a
`bias of at least two orders of magnitude against the incorpo-
`ration of 8-oxo-dGTP, rather than dTTP, opposite template
`adenines in DNA (28).
`The GO system that has been characterized for E. coli
`demonstrates that the cell goes to great lengths to prevent
`mutations due to GO adducts in DNA or the nucleotide pool.
`Its defense begins with the enzymatic and nonenzymatic
`systems that work to prevent active oxygen species from
`damaging DNA. Active oxygen species that escape the
`primary defenses can damage nucleic acids (19, 41). A
`second line of defense acts to eliminate this damage. MutM
`and MutT are typical of this second line of defense. The
`MutY protein and DNA polymerases provide yet another
`level of defense against the mutagenic potential of the GO
`adduct in DNA or the nucleotide pool.
`The GO system is critical to the maintenance of replication
`fidelity. A mutM mutY double mutant has a mutation rate
`that is of the same order of magnitude as the mutation rate
`observed when the polymerase III proofreading function is
`disabled, and it is significantly higher than the mutation rate
`of a strain lacking the methyl-directed mismatch repair
`system (31). The mutation rate of a strain lacking the GO
`system provides convincing evidence that active oxygen
`species pose a significant threat to the cell.
`The GO lesion is ubiquitous in nature and represents one
`of the most stable products of oxidative damage to DNA (17,
`19). While replication past a GO adduct has been tested for
`only a limited number of polymerases, all those tested
`misincorporate A opposite GO lesions in DNA to some
`extent (36, 37, 44, 50). These include both eukaryotic and
`prokaryotic polymerases. Evidence for repair proteins in
`higher eukaryotes similar to the ones characterized for E.
`coli is already beginning to emerge. Proteins with activities
`similar to those of MutM (29) and MutY (52) have been
`reported to exist in mammalian cells. Thus, the GO system
`may play a crucial role in maintaining replication fidelity in a
`wide range of organisms.
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