UV Radiation and Spontaneous Mutagenesis

Kendric C. Smith

Emeritus Professor, Radiation Oncology (Radiation Biology)
Stanford University School of Medicine
800 Blossom Hill Road, Unit R169, Los Gatos, CA 95032
kendric@stanford.edu
web.stanford.edu/~kendric/

As late as 1944, most scientists thought that proteins carried the genetic information. The general acceptance of DNA as the carrier of genetic information came only after the paper by Avery et al. (1944), which demonstrated the transformation of pneumococcus by purified DNA. However, many years earlier, photobiologists had information that demonstrated conclusively the importance of nucleic acid in both radiation-induced lethality and mutagenesis. In 1930, Gates published an action spectrum for the killing of bacteria that showed that nucleic acid, and not protein, was the target for lethality after UV irradiation. In 1939, the laboratories of Hollander and of Knapp published action spectra for the production of mutations by UV radiation (reviewed in Zelle and Hollaender, 1955); nucleic acid was implicated as the target for UV-radiation mutagenesis. Therefore, photobiologists had data that implicated DNA as the carrier of genetic information 5-14 years before this concept was accepted by the general scientific community.

Photobiologists need better public relations activities. It would be good if the different photobiology societies around the world would devote more time to the education of non-photobiologists about the important contributions that photobiologists make to science and society.


The Mutant Frequency Response (MFR)
The UV radiation MFR curve for Escherichia coli K-12 uvrB5 has been resolved into three components, which are suggested to be the result of three independent mutagenic mechanisms. They are: (1) a "one-hit" mechanism that produces the linear MFR at UV radiation fluences of 0-0.5 J/m2, but which operates at least up to 6 J/m2; (2) a "two-hit" mechanism that yields a fluence-squared MFR at fluences greater than ~0.5 J/m2; and (3) a kinetically complex (KC) process (previously called a ?-hit process) that is observed only between 1 and 3 J/m2. The 2-hit and KC mechanisms are associated with suppressor mutant production, and the one-hit mechanism is associated with back mutant production (Sargentini and Smith, 1979; Sargentini et al., 1982). Clearly, a 1-hit mutation response only requires that a specific lesion be produced in the DNA. For 2-hit mutagenesis, a number of mechanisms are possible, e.g., a DNA double-strand break, or overlapping DNA daughter-strand gaps (see below).


How Does UV Radiation Produce Mutations?
Cells are not just physical targets in which mutations are fixed instantly upon irradiation. Rather, it is what a cell does or does not do to the damage that determines whether it will result in a mutation. The first indication that this was true was the fact that post-irradiation treatments have a marked effect both on lethality and on the yield of mutations.

Roberts and Aldous (1949) showed that holding UV-irradiated E. coli B in non-nutrient liquid medium before plating on solid nutrient medium resulted in an enhancement of survival. This phenomenon has been termed liquid holding recover (LHR). It has been concluded both from genetic and biochemical evidence that the major process that occurs during LHR is nucleotide excision repair. The greatest amount of LHR is observed in a recA strain (Tang and Smith, 1980). It is suggested that the absence of the recA function permits excision repair to go to completion during LHR without interference by replication and recombination (i.e., postreplication repair).

Doudney's laboratory has provided information on the postirradiation modification of the yield of UV radiation-induced mutations (reviewed in Doudney, 1968). He coined the phrase "mutation frequency decline" (MFD), for the situation where there is a marked decrease in the yield of certain types of mutants if protein synthesis is transiently inhibited after UV irradiation. In 1968, Bridges and Munson wrote that "Of 'mutation frequency decline' (MFD) one is inclined to say that there can be few phenomena about which more is known and less is understood."

MFD was interpreted as an excision repair anomaly uniquely affecting nonsense suppressor mutations induced in certain tRNA genes. More recently, MFD has been linked to the transcription-coupled rapid repair of the UV radiation damage on the template strand of active genes (Selby and Sancar, 1993, 1994; Witkin, 1994).


SOS Response
MFD has focused our attention on the fact that radiation-induced mutations are not the immediate result of the actions of the radiation, rather, mutations are the result of how cells handle or mishandle radiation-induced DNA lesions. Conclusive proof of his concept came with the observations by Witkin (1967, 1969) that certain mutants of E. coli, i.e., those with mutations in the lexA and recA genes, could be killed, but could not be mutated by UV irradiation, and the concept of error-prone translesion DNA synthesis was born. This was further expanded by Radman (1974) into the SOS hypothesis, which states that DNA damage induces a set of genes required for survival and mutagenesis.

The RecA protein is activated by a DNA damage signal, probably the sudden increase in single-stranded DNA due to the blockage of DNA synthesis (e.g., Sassanfar and Roberts, 1990). The activated RecA protein (RecA*) then activates the LexA protein for autocleavage (Zhang et al., 2010). The LexA protein is the repressor for a set of 40 or so SOS genes, including umuC and umuD, thus causing the induction and expression of the SOS response (Kato and Shinoura, 1977; Steinborn, 1978). RecA* activates the cleavage of UmuD to generate UmuD', which associates with UmuC to form UmuD'2C, known as DNA polymerase V (Pol V). In the presence of RecA*, Pol V synthesizes DNA past replication-blocking lesions in a process known as translesion synthesis (TLS). Because TLS by Pol V is extremely inaccurate, it produces a huge increase in mutagenesis. However, once the majority of replication blocks are removed, either by the direct repair of the DNA or are tolerated by TLS, RecA is no longer activated, resulting in the repression of the SOS response (reviewed in Patel et al., 2010).

However, mutations in umuC or umuD (Pol V) only render cells slightly sensitive to killing by UV irradiation. Although non-mutable by UV radiation, umuC and umuD strains are still partially mutable by gamma-irradiation (Sargentini and Smith 1989; and references therein). In fact, umuC blocks all oxygen-dependent base-substitution gamma-radiation mutagenesis, but only a portion of oxygen-independent mutagenesis. Therefore, while all base-substitution mutations produced by UV irradiation are under the control of the umuCD genes, only a portion of the gamma-radiation-induced base-substitution-mutations appear to be umuCD-dependent (Sargentini and Smith, 1989). Other DNA polymerases are also known to contribute to UV mutagenesis (see below).

It should be noted that UV-radiation mutagenesis shows 1-hit kinetics at low doses (Sargentini and Smith, 1979). One-hit kinetics do not fit easily into the current dogma of inducible SOS mutagenesis.


Mechanisms of Mutagenic Translesion DNA Synthesis
There are several models to explain how DNA replication can resume at a blockage caused by a non-instructional lesion in E. coli (e.g., Echols and Goodman, 1990): (1) Polymerases are induced (or modified) that have lower fidelity (e.g., Pol II and Pol I*). (2) RecA protein itself can relax the fidelity of Pol III. In this regard, it is of interest that the overproduction of the epsilon subunit (i.e., the editing function) of Pol III counteracts the SOS mutagenic response of E. coli (Jonczyk et al., 1988), and the absence of the epsilon subunit (mutD) causes a huge increase in spontaneous mutations (Fowler et al., 1986; Piechocki et al., 1986) (see section on Spontaneous Mutations below). (3) Pol IV (dinB) exhibits no proofreading activity, has a strictly distributive mode of synthesis (i.e., just one dNMP for each cycle of binding to the DNA substrate), and has a clear propensity to elongate misaligned (bulged) primer/template structures (Wagner et al., 1999). (4) Pol V (umuC umuD) was the first polymerase to be associated with the SOS response (see section on SOS Response, above).

Perhaps the best-studied case of translesion synthesis involves AP sites (apurinic/apyrimidinic sites), which are known to be mutagenic (e.g., Schaaper and Loeb, 1981; Loeb and Preston, 1986). While AP sites are clearly non-coding lesions and are subject to repair processes (i.e., by AP endonucleases; Lindahl, 1990), DNA polymerase occasionally handles these lesions simply by introducing an adenine opposite an AP site. In some cases, adenine will be the correct base, but in most cases it will not be correct, and will lead to a mutation. dATP is also preferentially inserted opposite a number of bulky chemical adducts to DNA (e.g., aminofluorene, aflatoxin). This so-called "A Rule" of mutagen specificity has been reviewed (Strauss, 1991).

What are the Mutagenic DNA Repair Processes?
In general, DNA repair processes that can occur in the dark can be divided into two major categories, i.e., those processes that do not require DNA replication, and those that do. In the former category are nucleotide excision repair (see module on Excision Repair) and base excision repair (Seeberg et al., 1995). The repair system that requires DNA replication is postreplication repair (Smith, 2004; see module on Recombinational DNA Repair). Since mutations that block nucleotide excision repair enhance UV radiation mutagenesis (Hill, 1965), it suggested that excision repair is much less mutagenic than is postreplication repair (Witkin, 1976).

Nucleotide excision repair has a component that is recA dependent (Cooper and Hanawalt, 1972; Youngs et al., 1974), and is mutagenic (Nishioka and Doudney, 1970; Bridges and Mottershead, 1971). Cells with aligned chromosomes (i.e., not in the process of replication) show no recA-dependent excision repair, since no sister duplexes are present. The gap-filling step of recA-dependent excision repair is proposed to be analogous to the strand transfer mechanism that occurs during gap filling by postreplication repair (Smith and Sharma, 1987).

There is a minor pathway of postreplication repair that is umuC dependent (Wang and Smith, 1985). Presumably this is the pathway of postreplication repair that produces mutations after UV irradiation.


What Types of DNA Lesions are Mutagenic?

Pyrimidine Dimers and (6-4)-Adducts. Since photoreactivation (i.e., the enzymatic splitting of pyrimidine dimers in the presence of light; see module on Photoreactivation) is specific for the repair of cyclobutane-type pyrimidine dimers, and since photoreactivation greatly reduces the yield of UV-radiation-induced mutations, it has been concluded that pyrimidine dimers are mutagenic (e.g., Witkin, 1976). In addition, the irradiation and photoreactivation of the F-factor of E. coli prior to its single-strand transfer to recipient cells showed clearly that the premutagenic lesion was the cyclobutane-type pyrimidine dimer (Kunz and Glickman, 1984; Lawrence et al., 1985).

On the other hand, the measurement of pyrimidine dimers and (6-4)-adducts at the DNA sequence level in the lacI gene showed that the UV-radiation-induced mutation "hotspots" occurred at photoproduct hotspots, at which pyrimidine dimers were slightly more frequent than at other sites, but where (6-4)-adducts were greatly elevated (Brash and Haseltine, 1982). Later work has confirmed the fact that at certain locations the (6-4)-adducts are the major mutagenic lesion (Glickman et al., 1986b).

G:C -> A:T transitions predominate after UV irradiation. In E. coli the
(6-4)-photoproduct may be more important for mutagenesis, while the pyrimidine dimer may be more important in mammalian cells. In human cells, mutations occur at the C of a TC, CT, or CC pyrimidine dimer, but not at TT dimers, and also occur at the C of TC and CC (6-4)-adducts (reviewed by Brash, 1988).

Therefore, as with survival, no one UV-radiation-induced lesion can be assigned as the one and only mutagenic lesion. Under certain experimental conditions, and in certain base sequences within a gene, pyrimidine dimers can be the most important mutagenic lesions, however, under other experimental conditions, and at other base sequences (e.g., CC sites), the (6-4)-adduct can be the most important. Furthermore, purine photoproducts have been identified, and have been implicated in mutagenesis (reviewed in Brash, 1988). Therefore, statements about the relative importance of different photoproducts in lethality and mutagenesis must be assessed on an experiment by experiment basis.

Overlapping Daughter-Strand Gaps. Since UV-radiation-induced mutations show 2-hit kinetics at high doses, i.e., they are produced as a function of the square of the dose, there has been much discussion as to what these two radiation "hits" are at the molecular level (e.g., Witkin, 1976). Clearly, at least one hit must be in the gene to be mutated, and the second hit has been considered to be involved in the induction of the SOS response. Another mechanism for producing mutations that require 2-hits is the formation of two closely spaced lesions (one on each DNA strand), which lead to the formation of overlapping daughter-strand gaps during postreplication repair (Wang and Smith, 1986a,b). Since overlapping daughter-strand gaps cannot be repaired by the usual gap-filling model of postreplication repair, it has been reasoned that such a lesion may be highly mutagenic (Sedgwick, 1976).

DNA Double-Strand Breaks. While UV irradiation does not produce DNA double-strand breaks directly, they can be formed as a consequence of the inefficient repair of overlapping excision gaps (Bonura and Smith, 1975), and of overlapping daughter-strand gaps (Wang and Smith, 1986a,b) (see module on DNA Double-Strand Breaks). It has been shown that the gamma-radiation-induction of long-deletion mutations is the consequence of the repair of DNA double-strand breaks by the recB-dependent pathway, but not by the recF-dependent pathway, for the repair of DNA double-strand breaks (Sargentini and Smith, 1992).

DNA-Protein Cross-Links. The formation of DNA-protein cross-links has been shown to be of significance in the killing of E. coli both by UV irradiation at 254 nm (Smith et al., 1966), and by irradiation with visible light in the presence of such photodynamic agents as methylene blue and acridine orange (p. 188 in Smith and Hanawalt, 1969). The chemistry of DNA-protein cross-links is reviewed in a module on DNA-Protein Cross-links. If cells are UV irradiated while frozen, they are about 5-fold more sensitive to killing. Under these conditions the yield of thymine dimers approaches zero, and the yield of DNA-protein cross-links is greatly enhanced, suggesting that the enhanced yield of DNA-protein cross-links is the cause of the enhanced lethality. Frozen E. coli are also much more mutable by UV irradiation (Ashwood-Smith and Bridges, 1966), suggesting that DNA-protein cross-links are highly mutagenic lesions.


How Are Mutations Distributed Along The DNA?
In general, UV irradiation produces mutations along a gene in a non-random manner, i.e., mutations are observed at certain base pairs more frequently than at others (e.g., Coulondre and Miller, 1977). The bases that show a higher frequency of mutations are called "hot spots". By contrast, ionizing irradiation produces many fewer hot spots (e.g., Kato et al., 1985). These results are quite consistent with what we know about the photochemistry and radiation chemistry of DNA, i.e., UV radiation produces a preponderance of alterations in the pyrimidines, and the large majority of these products involve the linking of two adjacent pyrimidines. However, ionizing radiation produces damage in both the purines and the pyrimidines, and it is generally monomolecular in nature. Therefore, the hot spots for mutagenesis after UV irradiation generally occur in the DNA sequence where pyrimidine dimers and pyrimidine adducts can be formed.

However, not all adjacent pyrimidines in a gene show the same mutation frequency after UV irradiation. This has led to the realization that the nature of the bases adjacent to the two pyrimidines in question are very important in determining which of the adjacent pyrimidine pairs will become mutated. This has been called the effect of DNA "context" on mutagenesis (e.g., Drobetsky et al., 1987).


Spontaneous Mutagenesis
The genetic control of spontaneous mutagenesis is qualitatively similar to the genetic control of UV radiation mutagenesis (Sargentini and Smith, 1981, 1985). Spontaneous mutations are “the net result of all that can go wrong with DNA during the life cycle of an organism” (Glickman et al., 1986a). All types of mutations are produced spontaneously, i.e., base substitutions, frameshifts, insertions and deletions. However, few papers have appeared that are devoted exclusively to the study of the mechanisms of spontaneous mutagenesis, and of the subtle experimental factors that affect the types and frequencies of specific spontaneous mutations. This is unfortunate because spontaneous mutagenesis appears to play a major role in evolution, aging, and carcinogenesis (Smith, 1992).

Much of spontaneous mutagenesis in E. coli is due to error-prone DNA repair. The umuC mutation drastically reduces spontaneous mutagenesis. It was proposed that the low level of spontaneous mutagenesis observed in the recA, lexA and umuC strains is due to errors made during DNA replication, while the enhanced level of spontaneous mutagenesis observed in the wild-type strain, and especially in the uvrA and uvrB strains, is due to excisable lesions that are produced in the DNA by normal metabolic reactions, and that such unexcised lesions induce mutations via error-prone DNA repair (Sargentini and Smith, 1981).

As with UV radiation mutagenesis, spontaneous mutagenesis also shows "hot spots". There is enhanced mutagenesis at G-C sites, and enhanced mutagenesis when G or C are the nearest neighbors (Sargentini and Smith, 1994).


Summary
Photobiologists knew from the action spectra for the killing of bacteria that DNA carried the genetic information of a cell long before the general scientific community deduced this from transformation studies published in 1944. Furthermore, most of our current knowledge about the molecular basis and genetic control of mutagenesis has come from the work of UV radiation photobiologists.

The first leap in our understanding about mutagenesis came from the observations that mutagenesis is not due to the immediate effects of radiation on cells, but rather mutations are produced as the consequence of how cells mishandle the DNA damage via replication, repair, and recombination. The next leap came from the observation that, in bacteria, this error-prone handling of DNA damage is, in part, a radiation-inducible process.

Studies on UV radiation mutagenesis emphasize the metabolic and genetic control of mutagenesis, what types of DNA lesions are mutagenic and by what mechanisms, and the effect of neighboring nucleotides on the induction of a lesion in a specific nucleotide (e.g., "hot spots"), and on the multiple mechanisms for the incorrect handling of DNA lesions by replication, repair, and recombination.


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[NOTE: Papers by the author are available as PDF files.]

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