Cell Antibiotics UV radiation Arabidopsis, where stress causes increased homologous recombination rates in at least four generations of the progeny of treated plants(Molinier et aL., 2006) error rates during DNA replication. In the Bacillus subtilis K-state"response, stationary-phase cells become com- petent after synthesizing specific complexes that mediate suggested that the K-state is required to provide a tem replication fork plate for repairing damaged dNa that accumulates during RecA Re tationary phase(Berka et aL., 2002). However, depending Nucleofilament on the dna nearby, the uptake of foreign DNA could also increase genetic variability in stressed cells, and in human c ed to enable rapid ac Yet another mechanism for increasing a population's genetic variability under stressful conditions is exhibited P in organisms that increase the frequency of sexual repro- Pol IV Pol lV Error-prone DNA replicases evolutionary benefit of sexual reproduction remains atopic of debate, certain experiments indicate that sex may in- Increased mutation rates eed increase phenotypic variability in times of stres (for an example, see Greig et al., 1998). The choice of sex- creased phenotypic variability uaL, as opposed to asexual, reproductive strategies pro- a population during hardship; individual organisms essen- Figure 4. The SOS Pathway in E co tially gamble that their offspring will be more fit than they ns of dNa damage or perturbation lead to stalling and dis- are due to a novel combination of alleles, and the specie sociation of the replication machinery Single-stranded DNA is quickly as a whole enjoys increased genetic variability stabilized by the recA protein, and this nucleoprotein filament induces ity of LexA cleavage of LexA relieves ion of the 43 genes in the sos regulon, which are involved in various Directed Mutagenesis Revisited? DNA-repair processes. In particular, a special category of DNA poly. In some cases, organisms seem able to change ed upon SOS induction. These polymerases can by- timing and focus(location) of phenotypic variabi pass irregularities at damaged sites in the DNA However, they sho sponse to the environment. For example, in E co pression of genes in response to nutritional stress appears NA polymerases, thus eaming them the name"er to result in a specific increase in mutation rates of the cod ases"or"mutases. DNa damage is the best known inducer of the ing sequences in question, apparently due to the expo- at are not directly related to DNA damage also activate an Sos re- sure of single-stranded dna during the transcriptional ponse. These include starvation, exposure to antibiotics such as i- lactams, and exposure to physical stress such as elevated hydrostatic pears that the organism's production of genetic variation pressure (for a recent review, see Aertsen and Michiels, 2006). Al- is somewhat biased toward regions of the genome most ough activation of the sos pathway has been demonstrated ikely to be involved in reducing the stressful situation these cases, the exact trigger of the pathway remains unknown. It is This, of course, is very similar to the suggestion by Cairns possible that these stresses, through a yet-unknown mechanism, cause dna damage that results in sOS activation In the case of star and coworkers noted above(Cairns et al., 1988), and it is vation, for example, it has been suggested that the lack of nutrients unclear to us whether alternative explanations(such as the selective amplification of the target sequences that may (Bjedov et al., 2003).Alterna- explain Cairns' s observations) could account for the phe tively, the sos pathway may also be triggered by more specializer nomena described here. In any case, evidence is accumu- stress-sensing mechanisms, as seems to be the case for B-lactam ex lating that some types of stress result in mutagen hydrostatic pressure, which relies on the MrrlV restriction endonucle- recombination targeted to derepressed loci, which dem onstrates environmental targeting of genetic variability (whatever the underlying mechanism that exhibit the phenotype. Instead, the mechanism In mammals. at least two mechanisms have been de appears to be more complex and may involve epigenetic scribed that increase local mutation rates in response to alterations as irradiation also significant reduc environmental conditions. Perhaps the best-known sys the levels of methyltransferases in(nonexposed tem is"somatic hypermutation, where activated B cells der tissue. (Barber et al., 2002; Koturbash et al express activation-induced cytidine deaminase, which re- A similar phenomenon was recently described in sults in an increase of six orders of magnitude inC- T Cell 128, 655-668, February 23, 2007 @2007 Elsevier Inc. 663that exhibit the phenotype. Instead, the mechanism appears to be more complex and may involve epigenetic alterations, as irradiation also causes a significant reduc￾tion in the levels of methyltransferases in (nonexposed) bystander tissue. (Barber et al., 2002; Koturbash et al., 2006). A similar phenomenon was recently described in Arabidopsis, where stress causes increased homologous recombination rates in at least four generations of the progeny of treated plants (Molinier et al., 2006). Induced mutagenesis may not always rely on increased error rates during DNA replication. In the Bacillus subtilis ‘‘K-state’’ response, stationary-phase cells become com￾petent after synthesizing specific complexes that mediate the uptake of foreign DNA (Hahn et al., 2005). It has been suggested that the K-state is required to provide a tem￾plate for repairing damaged DNA that accumulates during stationary phase (Berka et al., 2002). However, depending on the DNA nearby, the uptake of foreign DNA could also increase genetic variability in stressed cells, and in human pathogens this is feared to enable rapid acquisition of antibiotic resistance (Prudhomme et al., 2006). Yet another mechanism for increasing a population’s genetic variability under stressful conditions is exhibited in organisms that increase the frequency of sexual repro￾duction under stressful conditions. Although the exact evolutionary benefit of sexual reproduction remains a topic of debate, certain experiments indicate that sex may in￾deed increase phenotypic variability in times of stress (for an example, see Greig et al., 1998). The choice of sex￾ual, as opposed to asexual, reproductive strategies pro￾vides a species with a way to increase the variation in a population during hardship; individual organisms essen￾tially gamble that their offspring will be more fit than they are due to a novel combination of alleles, and the species as a whole enjoys increased genetic variability. Directed Mutagenesis Revisited? In some cases, organisms seem able to change both the timing and focus (location) of phenotypic variability in re￾sponse to the environment. For example, in E. coli, dere￾pression of genes in response to nutritional stress appears to result in a specific increase in mutation rates of the cod￾ing sequences in question, apparently due to the expo￾sure of single-stranded DNA during the transcriptional process (see Wright, 2004 for a review). Here, then, it ap￾pears that the organism’s production of genetic variation is somewhat biased toward regions of the genome most likely to be involved in reducing the stressful situation. This, of course, is very similar to the suggestion by Cairns and coworkers noted above (Cairns et al., 1988), and it is unclear to us whether alternative explanations (such as the selective amplification of the target sequences that may explain Cairns’s observations) could account for the phe￾nomena described here. In any case, evidence is accumu￾lating that some types of stress result in mutagenesis or recombination targeted to derepressed loci, which dem￾onstrates environmental targeting of genetic variability (whatever the underlying mechanism). In mammals, at least two mechanisms have been de￾scribed that increase local mutation rates in response to environmental conditions. Perhaps the best-known sys￾tem is ‘‘somatic hypermutation,’’ where activated B cells express activation-induced cytidine deaminase, which re￾sults in an increase of six orders of magnitude in C / T Figure 4. The SOS Pathway in E. coli Various forms of DNA damage or perturbation lead to stalling and dis￾sociation of the replication machinery. Single-stranded DNA is quickly stabilized by the RecA protein, and this nucleoprotein filament induces the autoproteolytic activity of LexA. Cleavage of LexA relieves repres￾sion of the 43 genes in the SOS regulon, which are involved in various DNA-repair processes. In particular, a special category of DNA poly￾merases is activated upon SOS induction. These polymerases can by￾pass irregularities at damaged sites in the DNA. However, they show error rates that are approximately 100-fold higher than those of normal DNA polymerases, thus earning them the name ‘‘error-prone polymer￾ases’’ or ‘‘mutases.’’ DNA damage is the best known inducer of the SOS pathway, but recent research shows that other forms of stress that are not directly related to DNA damage also activate an SOS re￾sponse. These include starvation, exposure to antibiotics such as b￾lactams, and exposure to physical stress such as elevated hydrostatic pressure (for a recent review, see Aertsen and Michiels, 2006). Al￾though activation of the SOS pathway has been demonstrated for these cases, the exact trigger of the pathway remains unknown. It is possible that these stresses, through a yet-unknown mechanism, cause DNA damage that results in SOS activation. In the case of star￾vation, for example, it has been suggested that the lack of nutrients may result in the intracellular accumulation of DNA-damaging agents and the decrease of DNA-repair enzymes (Bjedov et al., 2003). Alterna￾tively, the SOS pathway may also be triggered by more specialized stress-sensing mechanisms, as seems to be the case for b-lactam ex￾posure, which depends on the two-component system DbiB/A, and for hydrostatic pressure, which relies on the MrrIV restriction endonucle￾ase (Aertsen and Michiels, 2006). Cell 128, 655–668, February 23, 2007 ª2007 Elsevier Inc. 663