Frameshift mutation, microsatellites and mismatch repair1

Mutation Research 437 Ž1999. 195–203 www.elsevier.comrlocaterreviewsmr Community address: www.elsevier.comrlocatermutres

Reflections in Mutation Research

Frameshift mutation, microsatellites and mismatch repair Bernard S. Strauss

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Department of Molecular Genetics and Cell Biology, UniÕersity of Chicago, 920 East 58th Street, Chicago, IL 60637 USA Accepted 18 August 1998

Abstract The structure of eukaryotic DNA, with its repeated sequences, makes base addition and loss a major obstacle to the maintenance of genetic stability. As compared to the bacteria, much of the mismatch repair capacity of the eukaryotic cell must be devoted to the surveillance of frameshift changes. Any alteration in the activity of proteins which recognize frameshifts or which hold the DNA in place during replication is likely to result in genomic instability. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Frameshift mutation; Mismatch repair; Homopolymer runs; DNA polymerase; Genetic stability

1. Introduction Frameshift mutations are base additions or deletions within the coding region of a gene disturbing the reading frame so that the entire set of triplets downstream of the addition or deletion is altered. In many cases, the addition or deletion results in the exposure of in-frame termination sequences which truncate the product. Frameshift mutations are therefore likely to result in more severe phenotypic effects than do many of the base changes which result in either silent or conservative changes in protein products. Since there is nothing at the nucleic acid level to distinguish frameshifts within coding regions

) Tel.: q1-773-702-1628; fax: q1-773-702-3172; E-mail: [email protected] 1 This article is part of the Reflections in Mutation Research series. To suggest topics and authors for Reflections, readers should contact the series editors, G.R. Hoffmann Žghoffmann @holycross.edu. or D.G. MacPhee Ž[email protected]..

from other base additions or deletions it is convenient to refer to all simple Žone or two base. additions or deletions as ‘‘frameshifts’’. 2

2. Base substitutions and frameshifts The recognition that there is a class of mutation characterized by the addition or loss of one or a few nucleotides depends on the demonstration that mutations can be Žand often are. the result of single nucleotide changes within the DNA. The evidence that this is so derives in large part from the experiments of Benzer and Freese w1x on the rII locus of bacteriophage T4. Benzer’s experiments are cited in

2 As pointed out by Dr. Gordenin, this convenience can be illusory when dealing with triplet repeats in which addition or deletion of a repeating unit occur with maintenance of the reading frame.

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standard textbooks of genetics as defining the nature of the gene. His work showed that recombination could separate mutations which his calculations implied were separated by only single nucleotides. He and his colleagues also used a variety of chemical mutagens to show that the sites of mutation induced by chemicals differed from the spontaneous location and that certain regions of the genome were more mutable than others, the so-called ‘‘hot spots’’ w1x. Then, Ernst Freese 3 who had worked with Benzer on the phage T4 system w1x found that mutations induced by base analogs were revertible only by other base analogs and not by mutagens of the acridine family. Freese w2x concluded that there were two kinds of mutations, both characterized by base changes: transitions in which pyrimidines were replaced by pyrimidines Žand purines by purines. and transversions in which purines were replaced by pyrimidines or pyrimidines by purines. He supposed that bromouracil and aminopurine induced transitions, acridine induced transversions and that spontaneous mutations were a mixture of both. A few years later, Brenner et al. w3x at the MRC reinterpreted this data and argued on the basis of their failure to obtain ‘‘leaky’’ mutants with proflavin that the changes Freese had interpreted as transversions were actually frameshift mutations. An additional argument was the finding that none of the supposed ‘‘transversions’’ mapped at exactly the same site as any of the transitions — which was not understandable if they were both simple base substitutions 4 . Understanding frameshift mutations permitted the MRC group to demonstrate by purely genetic techniques that the

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Freese had been trained as a solid state physicist. He objected to the need for physicists to work in large teams and he also felt that new discoveries were hard to come by in physics. In contrast, he told me after a seminar in Chicago, biology in the 1950s seemed to promise unlimited opportunity! 4 Benzer was highly annoyed — at least at first. He visited the University of Chicago in 1961 to receive the Ricketts award. I knew him slightly and talked to him after the lecture. He was indignant at the idea that his former collaborator had been corrected and at that time was not ready to accept the deductions of the Cambridge group which were also based on indirect evidence. Of course both groups were leading the genetics community to a more molecular understanding of what happened in mutation. Brenner also happened to be correct.

codons needed to be triplets w4x and they did this by showing that the third mutation in a series of Žq1 or y1. mutation restored genetic function. The evidence that acridine induced mutations were mostly frameshifts came from the demonstration that mutations could be Žarbitrarily. put into two groups: Žq1. and Žy1. and that combination of Žq1. and Žy1. mutations gave a suppressed strain that was almost normal w5x. 5 Biochemical evidence for this hypothesis came when Streisinger et al. w6x isolated and determined the amino acid sequence of bacteriophage lysozyme mutants. The suppressed mutants had a normal sequence except for a group of five amino acids. Given the original and substituted amino acid sequence, the sequence of nucleotides involved could be uniquely deduced. 6 Streisinger et al. then suggested the following: ‘‘frameshift mutation would involve the insertion of a base or a base doublet, identical to an adjacent one already present in the wild-type DNA. The insertion would be most likely to occur in a region of repeating bases or base doublets through the pairing of a set of bases in one chain of the DNA molecule with the wrong, but complementary set in the other chain.’’ This is the ‘‘slippage’’ model for frameshifts although Streisinger et al. does not use the term in the 1966 paper. It was not immediately clear what aberrant biochemical process produced frameshift mutation nor what the role of the acridine mutagens might be. For some years it appeared that acridine mutagenesis was restricted to the bacteriophage and that bacteria were immune. On structural grounds, Lerman w7x had suggested that frameshifts should occur by recombination and this remained a reasonable hypothesis during the 1960s. The role of recombination was supported by the observation from Adelberg’s laboratory w8x that proflavin mutagenesis could be observed in a mating mixture of bacteria but not in haploids

5 Although the experiments were announced in 1961, the full paper giving the details of how the frameshift experiments were done was not published until 1967 w5x! 6 It is hard to remember but there was a period in which amino acid sequences in protein could be determined — with difficulty — but nucleotide sequences were just not experimentally accessible!

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and that diploidy for the gene to be mutated was necessary. However, at about the same time it was shown that a group of acridine derivatives Žthe ICR compounds. that covalently bound to DNA were highly efficient frameshift mutagens for Escherichia coli w9x. In addition it was observed that frameshift mutation induced in E. coli by ICR-191 or 5aminoacridine occurred at the time of replication Žas determined with synchronized cultures., was increased in nucleotide excision repair defective cultures and was not decreased in recAy and recBy strains w10x. Newton et al. w10x concluded that Žinduced. frameshift mutation was somehow associated with replication. In fact, this is where we are today. Given the right conditions, susceptibility to frameshift mutagens is found in all organisms and recombination is not required. There is likely more than one mechanism of frameshift mutation w11x but all are associated with replication at some stage. Not all mechanisms need be associated with slippage, even at repeated sequences. Some of the sites for acridine-induced mutation of T4 bacteriophage correspond to the sites at which topoisomerase breaks DNA in the presence of acridine w12x, and although the site is repetitive, slippage does not seem to be involved w13x. Slippage does occur in the replication of DNA with repeated elements by polymerases in vitro but such experiments need not invariably reflect the in vivo situation w11x. The Streisinger model does focus on repeated nucleotide sequences in DNA. It had been recognized from the earliest studies on E. coli DNA polymerase I that large oligonucleotide polymers could be synthesized without template after a long lag period. It was presumed that this synthesis was based on polynucleotide contaminants in the enzyme preparations that could serve as templates w14x. Added template-primers as small as six base pairs could generate large polymers by what Kornberg w15x called reiterative replication. A ‘‘scheme of reiteration and slippage’’ was provided to account for these results which require the 5X ™ 3X exonuclease activity of the enzyme. These early observations have been repeated and their possible biological role in the synthesis of repeated elements has been commented upon w16x. At the time the early studies were done, the only repetitive sequence known in nature was the poly-dŽA–T. which makes up as much as a fourth of

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the total DNA in some species of crab and sediments in a CsCl as a satellite band separable from the main component of higher density Žsee Ref. w15x.. It was therefore not appreciated by biologists that these experiments illustrated an important property of the polymerases: that without associated protein they were permissive in allowing their substrates to slip. An estimate of the amount of slippage that occurs in each replication event in organisms can be obtained using mutants that are unable to repair slippage mistakes w17x. In E. coli, a mutant with no mismatch repair and with minimal proofreading makes about one frameshift per 100 cycles when replicating a run of 14ŽCA.s w18x. The rate is proportional to the length of the sequence being replicated in an experimental system in which repeats are inserted into the genome of single stranded M13 bacteriophage w19x. In yeast w20x and in phage T4 w21x, there is an exponential dependence on the length of the run.

3. The nature of eukaryotic DNA By the early 1970s our understanding of molecular genetics had become fairly sophisticated and the relationships between DNA, RNA and the protein products seemed clear w22,23x. 7 The bacterial systems were viewed as good models for what went on in eukaryotes. A major premise of molecular genetics as it was understood then was that there should be an absolute collinearity between the nucleotide sequence of a gene and the amino acids of the protein product w24x. This premise was coupled with the implicit assumption that since the genetic material is DNA, all DNA carries genetic information. There was the ‘‘scandal’’ of the very large amount of DNA contained in the nucleus of some amphibians but this DNA was considered a special case of ‘‘junk’’ DNA, left over from evolutionary experiments w25x. A gradual shift from bacteria to eukaryotes as experimental organisms coincided with a growing understanding of the complexity of eukaryotic DNAs. In 1977, the astounding discovery was made that large chunks of DNA were interspersed

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Crick called this relationship the ‘‘Central Dogma’’ of molecular biology.

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within the coding regions and that these intervening sequences or introns had to be spliced out of the RNA transcript to make functional message w26x. The rest of the eukaryotic genome contains multiple copies of a variety of DNA sequences, some apparently the remnants of retroviruses or retrotransposons that had inserted themselves into the genome w27x. In addition, the ability to sequence DNA led to the discovery that there were extensive runs of mononucleotides, dinucleotides, trinucleotides and even tetranucleotides scattered throughout the genome. There are more than 5000 dinucleotide repeat sequences in the human genome Žwhere the repeat is six or more. interspersed throughout the genome. Since these sequences are polymorphic they have served as the basis for mapping the mammalian genome w28x. To be used as markers they need to be stable. Nonetheless, they should be subject to slippage during replication and so be less stable than unique sequences. An average germinal mutation rate of 1.2 = 10y3 per locus per gamete per generation was reported for dinucleotide repeats but the authors cautioned that the figure might be inflated by somatic events w29x. Even this rate is quite stable considering the expected rates of slippage. Some mechanism must keep the variability of the repeated sequences within bounds since as indicated above, without such correction a replication of a run of 14 dinucleotide repeats leads to an error at least 1% of the time w18x!

4. The role of mismatch repair Recognition of how this is accomplished in eukaryotes came with the discovery that the instability of dinucleotide repeats is greatly enhanced in the colon carcinomas of individuals with an inherited susceptibility to non-polyposis colon carcinoma w30x. This phenomenon was termed microsatellite instability and was initially supposed to be due to an aberrant form of DNA replication in these tumors. It was, of course, an example of extensive frameshift mutation. It had been realized from the earliest investigations on the generalized mismatch repair system in bacteria Žinvolving the mutS, mutH, mutL and dam genes. that the system recognized and corrected frameshift mutations w31x. In particular, it had been

shown that mutants of yeast, deficient in mismatch repair, made numerous frameshifts in repeated sequences w32x. One of the investigators who had worked out the detailed biochemistry of mismatch repair in bacteria, Paul Modrich w33x, heard about these experiments and recognized that a deficiency in mismatch repair was likely to account for the microsatellite instability in tumors w30x. A simultaneous 8 discovery of the role of mismatch repair came from the laboratory of Richard Kolodner who had been working on mismatch repair homologs in yeast w34x. They had sequenced a yeast repair gene and found that a published sequence in the human genome included a homolog of their yeast repair genes and mapped at the same position as the gene responsible for the microsatellite instability w35x. It was then discovered that the tumors of such individuals were deficient in their ability to carry out mismatch repair because of a deficiency in one or the other of the mismatch repair proteins w34,36x. Although the mismatch repair systems in prokaryotes and eukaryotes are homologous, there are important differences w37x. Mismatch repair in bacteria is generally considered as happening after replication, during a window of time in which the parent strand can be distinguished from the newly synthesized daughter. In a very few prokaryotes such as E. coli the signal that distinguishes old from new strands is hemimethylation of adenines. Adenines in the newly synthesized strand at GATC sites are not methylated by the dam-encoded methylase until some time after replication. In eukaryotes Žand in fact many bacteria. methylation is not used and the signal is most likely a single strand break. In fact, whereas replication and mismatch repair are at least conceptually separable in prokaryotes, replication and mismatch repair may be linked in eukaryotes w38x. A second distinction in the mismatch repair systems of eukaryotes and prokaryotes is the occurrence of several mutS and mutL homologs in the eukaryotes, whereas single proteins carry out all the mismatch repair functions in bacteria. There is special-

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The Fishel paper was received by Cell on November 8, revised on November 18 and published in the December 3, 1993 issue. The Parsons paper was received by Cell on November 29th and published in the issue of December 17, 1993.

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ization in the different mutS analogs MSH2, MSH3 and MSH6 which act as heterodimers so that the MSH2rMSH3 dimer is more efficient at the recognition of loops caused by additions or deletions whereas the MSH2rMSH6 complex is most efficient at the recognition of base mismatches w39–41x. The mismatch repair system is limiting in E. coli even in exponential growth and the amount of mismatch repair falls precipitously as cells enter stationary phase w42x. In particular there is a 10-fold drop in the amount of mutS protein. E. coli deficient in proofreading are also deficient in mismatch repair because the system is saturated by the onslaught of errors w43x. The mononucleotide repeat sequences in prokaryotes are limited in size to about eight or less and are mostly found in coding regions w44,45x, probably because prokaryotes contain relatively little non-coding DNA. Much of the correction of replication errors is therefore due to the proofreading exonuclease which recognizes both single base mismatches and frameshifts in non-repeated w17x or in low repeat sequences w18,46x. In sharp contrast, the higher eukaryotes have many repeated sequences and in yeast the majority of the long sequences Ž) 8. are found in the non-coding regions w45x. It is an obvious speculation that the differentiation of the mismatch repair system in eukaryotes is due to the greater structural complexity of this DNA with one part of the mismatch repair apparatus being dedicated to keeping slippage in repeated sequences under control. Although both exonucleolytic proofreading and mismatch repair correct errors in newly synthesized DNA, only mismatch repair deficiencies have been convincingly associated with the instability of repeats. The mismatch repair system is uniquely adapted to the repair of additions or deletions in long repeated sequences since it has been shown both in vitro w46x and in vivo that proofreading plays a minor role in the prevention of mutations in the longer runs w18,20,32x.

5. The mechanism of slippage Mismatch repair and, depending on the size of the repair tract, exonucleolytic proofreading correct frameshift errors once made. The errors need to be

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made before being corrected. One can therefore ask what factors regulate the production of frameshifts? Actually, the question is, what are the factors which prevent slippage and frameshifting? Slippage is clearly a feature of all simple polymerization processes as discussed above w15x. Replicating systems in real organisms need to have some way of preventing the massive slippage that occurs in these simple experimental systems. A priori, both nucleic acid and protein structure must be involved. Consider what must happen for a frameshift mutation to occur during DNA synthesis across a region of repeated elements. First, there must be slippage. Elongation continues. However, the slipped intermediate can also slip back. If this reverse slippage occurs while DNA synthesis is still traversing the repeated tract, then no mutation will occur. However, if the bulge produced by slippage is stabilized long enough for DNA synthesis to proceed past the repeated region and into a region of unique sequence, then the bulge will be fixed since the growing point is now ‘‘anchored’’ by the unique sequences. Frameshifting is therefore the resultant of a competition between the rate of elongation and the stability of the DNA intermediate. One might therefore expect structures in which the extrahelical nucleotide structure is particularly stable to frameshift more readily than structures with an unstable extrahelical loop. A characteristic of the repeated sequences in yeast, humans, and C. elegans Žbut not E. coli or M. leprae . is the large contribution of runs of A’s Žor T’s. w44x. The overall composition of the genome is not sufficient to account for this overrepresentation of A and T w45x. The distribution of runs in coding regions is restricted by the amino acid code — a run of glycines ŽGGG. might not be tolerated. However, in non-coding regions the genome should be more permissive. Why should there be an excess of A runs? One possibility is that poly-A tracts play regulatory roles. Alternatively, A-enriched sequences might be parts of mobile DNAs or the tendency of polymerases to insert A’s at the site of damaged bases w47x might lead to an accumulation of this nucleotide. Yet an additional alternative is that runs of A:T are more likely to slip leading to expansions or that runs of A or T, once formed, are more stable. In E. coli, repeats of G’s and C’s were observed to frameshift more frequently than repeats of A’s in a

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mismatch repair deficient strain w48,49x. Runs of G and C may be less stable because the frameshift intermediate with extrahelical G’s and C’s is more stable. There is physical data to support this view w50x. Other kinetic properties of the elongating DNA are also likely to be involved in the production of frameshifts. For example, treatments which delay DNA chain progression are likely to result in deletions or additions of bases. One of the methods of delaying DNA synthesis is by the insertion of an incorrect base at some position in the DNA. This delays synthesis and, as suggested by Bebenek et al. w51x, a misalignment of the initially misinserted base could result in the generation of correct terminal base pairs which were then elongated. The alteration of a nucleotide by formation of an adduct which reduces the rate of elongation would have somewhat the same effect and in fact, misinsertions followed by frameshifts have been observed both in vitro and in vivo w52x. One of the most efficient frameshifting agents is acetyl aminofluorene which inhibits DNA synthesis and also seems to stabilize the frameshifted intermediate w53x. In fact, acetylaminofluorene and its action has become a paradigm for a frameshift mutagen. An aminofluorene adduct with the acetyl group removed is no longer a major block to DNA synthesis w54,55x and results in base substitution rather than frameshift mutations w56x. This cannot be the whole story since different polymerases behave differently in their ability to misinsert bases as compared to making errors by base dislocation w57x. In addition, the frequency with which a series of mutant T7 DNA polymerases produced UV-induced frameshifts in vitro correlated with the velocity with which they replicated a M13 template but not with their exonuclease activity w58x. The structure of the polymerase proteinŽs. itself might be expected to be important, particularly in the case of frameshifts at repeated sequences since one might expect the amino acids of the polymerase to interact with the individual bases to prevent the movements of the primer or template that result in slippage. This interaction would not necessarily be expected at the catalytic center. For example, as pointed out above, the longer the run of repeated units, the less the effect of proofreading w46x indicating that the slippage events need not occur at the

growing point Žor that the slippage ‘‘bulge’’ migrates away from the growing point.. Site directed mutagenesis studies with single protein polymerases illustrate these concepts. Substitution of alanine for other amino acids in the thumb domain of both HIV reverse transcriptase w59x and pol I w60x results in an enzyme which makes increased numbers of frameshifts. In contrast to the ‘‘simpler’’ polymerases which have been studied, most replicative polymerases of free living organisms are made of numerous subunits and the three dimensional structure and mode of interactions of these subunits is still being investigated. Mutations of the catalytic subunit of E.coli pol III leading to a frameshift mutator effect have been isolated w61,62x but it is still unknown how the mutator effect comes about. For example, a mutation leading to a decreased ability to bind and activate the proofreading subunit would lead to decreased proofreading and a mutator effect. The various domains of the E. coli polymerase are only beginning to be defined w63x. Mutations of the PCNA ‘‘clamp’’ result in a frameshift mutator effect in yeast. However, the data have been interpreted as meaning that this subunit interacts with the mismatch repair proteins independent of its role in replication because double, mismatch repairrPCNA mutants do not make many more mutations than the mismatch repair mutants w38,64x. Since the boundaries of replication and mismatch repair in eukaryotes are not sharply defined w38x, this conclusion may yet be modified.

6. Biological role of DNA frameshifts One of the more interesting features of modern biology is the demonstration of transient hypermutability occurring in populations of cells or of bacteria w65–68x. In the bacteria, the mutations that occur in stationary cells seem to be the result of changes in a subpopulation. To date, most investigators of this phenomenon have employed a strain carrying a plasmid with a revertible frameshift within a repeated sequence and it appears possible that the mechanism may involve a temporary failure in mismatch repair. In a possible similar manner, the accumulation of mutations in tumors may involve a hypermutable state w69–71x.

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One of the earliest papers on rapid mutagen identification by Ames et al. w72x is entitled: ‘‘Carcinogens as frameshift mutagens’’ as though there were something particularly carcinogenic in frameshift mutagens. It appears that he had it right! Several of the important tumor suppressor genes contain mononucleotide runs within the coding sequences w73–76x. These constitute ‘‘at-risk-motifs’’ ŽARMs. w77x which are targets for frameshift mutagenesis and are peculiarly sensitive to mismatch repair deficiency. One of the interesting illustrations is the finding of a mutation which predisposes to cancer by altering a base in the midst of a homonucleotide run thereby creating an ultrasensitive ARM w78x. Frameshift mutations, particularly frameshift mutations in repeated sequences appear as a major factor of eukaryotic life and the control of these mutations has probably resulted in the refinement of the mismatch repair systems of higher organisms. Acknowledgements The work from the authors laboratory was performed, in part, with support from the National Cancer Institute, National Institutes of Health ŽCA 32436.. I would like to thank Dr. Louise Prakash, Dr. Satya Prakash and Dr. Dmitry Gordenin for their comments on a draft of the manuscript. References w1x S. Benzer, E. Freese, Induction of specific mutations with 5-bromouracil, Proc. Natl. Acad. Sci. USA 44 Ž1958. 112– 119. w2x E. Freese, The difference between spontaneous and base-analogue induced mutations of phage T4, Proc. Natl. Acad. Sci. USA 45 Ž1959. 622–633. w3x S. Brenner, L. Barnett, F.H.C. Crick, A. Orgel, The theory of mutagenesis, J. Mol. Biol. 3 Ž1961. 121–124. w4x F.H.C. Crick, L. Barnett, S. Brenner, R.J. Watts-Tobin, General nature of the genetic code for proteins, Nature 192 Ž1961. 1227–1232. w5x L. Barnett, S. Brenner, F.H.C. Crick, R.G. Shulman, R.J. Watts-Tobin, Phase shift and other mutants in the first part of the rIIB cistron of bacteriophage T4, Philos. Trans. R. Soc., Ser. B 252 Ž1967. 487–560. w6x G. Streisinger, Y. Okada, J. Emrich, A. Newton, E. Tsugita, E. Terzhagi, M. Inouye, Frameshift mutations and the genetic code, Cold Spring Harbor Symp. Quant. Biol. 31 Ž1966. 77–84.

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w7x L.S. Lerman, The structure of the DNA–acridine complex, Proc. Natl. Acad. Sci. USA 49 Ž1963. 94–101. w8x S. Sesnowitz-Horn, E.A. Adelberg, Proflavin treatment of Escherichia coli: generation of frameshift mutation, Cold Spring Harbor Symp. Quant. Biol. 33 Ž1968. 393–402. w9x B.N. Ames, H.J. Whitfield Jr., Frameshift mutagenesis in Salmonella, Cold Spring Harbor Symp. Quant. Biol. 31 Ž1966. 221–225. w10x A. Newton, D. Masys, E. Leonardi, D. Wygal, Association of induced frameshift mutagenesis and DNA replication in Escherichia coli, Nat. New Biol. 236 Ž1972. 19–22. w11x L.S. Ripley, Frameshift mutation: determinants of specificity, Annu. Rev. Genet. 24 Ž1990. 189–213. w12x L.S. Ripley, J.S. Dubins, J.G. deBoer, D.M. DeMarini, A.M. Bogerd, K.N. Kreuzer, Hotspot sites for acridine-induced frameshift mutations in bacteriophage T4 correspond to sites of action of the T4 type II topoisomerase, J. Mol. Biol. 200 Ž1988. 665–680. w13x V.L. Kaiser, L.S. Ripley, DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4, Proc. Natl. Acad. Sci. USA 92 Ž1995. 2234–2238. w14x J.F. Burd, R.D. Wells, Effect of incubation conditions on the nucleotide sequence of DNA products of unprimed DNA polymerase reactions, J. Mol. Biol. 53 Ž1970. 435–459. w15x A. Kornberg, DNA Synthesis, Freeman, San Francisco, CA, 1974, ixq399. w16x C. Schlotterer, D. Tautz, Slippage synthesis of simple sequence DNA, Nucleic Acids Res. 20 Ž1992. 211–215. w17x R.M. Schaaper, Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli, J. Biol. Chem. 268 Ž1993. 23762–23765. w18x B.S. Strauss, D. Sagher, S. Acharya, Role of proofreading and mismatch repair in maintaining the stability of nucleotide repeats in DNA, Nucleic Acids Res. 25 Ž1997. 806–813. w19x G. Levinson, G. Gutman, High frequencies of short frameshifts in poly-CArTG tandem repeats borne by bacteriophage M13 in Escherichia coli K-12, Nucleic Acids Res. 15 Ž1987. 5323–5338. w20x H.T. Tran, J.D. Keen, M. Kricker, M.A. Resnick, D.A. Gordenin, Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants, Mol. Cell Biol. 17 Ž1997. 2859–2865. w21x D. Pribnow, D.C. Sigurdson, L. Gold, B.S. Singer, C. Napoli, J. Brosius, T.J. Dull, H.F. Noller, rII cistrons of bacteriophage T4. DNA sequence around the intercistronic divide and positions of genetic landmarks, J. Mol. Biol. 149 Ž1981. 337–376. w22x F.H.C. Crick, On protein synthesis, Symp. Soc. Exp. Biol. 12 Ž1958. 138–163. w23x F.H.C. Crick, Central dogma of molecular biology, Nature 227 Ž1970. 561–563. w24x G.S. Stent, Molecular Genetics. An Introductory Narrative, Freeman, San Francisco, CA, 1971, xviq650. w25x S. Ohno, So much ‘‘junk’’ DNA in our genome, Brookhaven Symp. Biol. 23 Ž1972. 366–370. w26x S.M. Berget, C. Moore, P.A. Sharp, Spliced segments at the

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