Environmental Factor, February 2009, National Institute of Environmental Health Sciences
Trainees Host Stress-Induced Mutagenesis Seminar
By Brian Chorley
On January 5, the NIEHS welcomed Susan Rosenberg, Ph.D., a professor at the Baylor College of Medicine, who conducted a thought-provoking seminar regarding DNA mutation in response to environmental stress. Libertad García Villada, Ph.D., a visiting fellow in the NIEHS Laboratory of Molecular Genetics (LMG) Spontaneous Mutation and DNA Repair Group, coordinated the morning's lecture. The seminar was part of an ongoing series of trainee-hosted speakers organized by members of the LMG Trainee Action Committee (TAC).
Rosenberg (http://www.bcm.edu/cmb/?pmid=2391) , an expert on bacterial models of mutation, has dedicated much of the past decade to understanding mechanisms of strand breakage, recombination and subsequent mutation in response to stress. Rosenberg's talk had an overarching theme of "what's interesting to us is genome instability - how it works and its implications for biology," which, she said, describes her laboratory's core mission.
Genetic variation in a population, Rosenberg explained, gives rise to enhanced adaptation in a changing environment, a concept that is the basis of modern evolutionary theory. She postulated that this variation may arise from two separate sources - pre-existing mutations that may confer adaptation as a stressor is applied or, intriguingly, mutagenesis that confers an adaptive response after a stressor is applied.
Rosenberg believes cells run programs that create mutations, some of which ultimately assist in adaptive response to the environment. She explained that when this idea first surfaced, many scientists worried that it supported the arcane notion of Lamarckian evolution - a theory popular in the 19th century that states adaptation is acquired through the concerted efforts of an organism, as in the archetypical scenario of a giraffe's evolving neck length to better reach the leaves of a tree. Although mutation itself is random, with no regard for what adaptation is required, Rosenberg said, "mutagenic response is not insensitive to the environment."
During her talk, Rosenberg concentrated on what she described as three core mechanistic principles of stress-induced mutagenesis, all of which may enhance cell or organism "evolvability." The first occurs when an organism senses maladaptation to its environment and switches to a mutagenic state induced by stress response. With the second, mutation is localized to small, presumably random regions of the genome, targeting local gene clusters and avoiding change to the genome in its entirety. The third involves the differentiation of cellular subpopulations that are transiently hypermutagenic.
Using bacterial models of growth-component deficiency adaptation, Rosenberg's laboratory generated data to support these theories. The investigators found in their models that mutagenesis primarily occurs in regions of double-strand break repair. However, mutation was not constant; rather, it happened only during periods of stress. Rosenberg discovered that the normal high-fidelity, non-mutagenic DNA repair is switched to low-fidelity, error-prone repair governed by the bacterial stress-response factor RpoS and mediation of the translesion synthesis (TLS) DNA polymerase DinB. Because mutation seems to be confined to areas of double-strand break repair, stress-induced mutagenesis is limited to those areas of the genome in which this type of damage has occurred.
According to Rosenberg, two additional signaling mechanisms mediate stress-induced mutagenesis in her models - the SOS and RpoE stress responses. When both are active along with the RpoS pathway, cells transition into a transient hypermutable state. Preliminary evidence generated by her laboratory suggests that these subpopulations are in a ready state and become responsively mutagenic, and therefore most adaptive, when an environmental stressor is applied. Rosenberg explained that little is known about this state and it may well be confined to certain bacteria; however, she said it is tantalizing to speculate about the existence of similar mechanisms in other cell populations.
Rosenberg envisions that her research will have implications beyond the mechanisms of bacterial evolution. An important human corollary is tumor cell responsiveness to chemotherapy. Cancer treatments are primarily anti-proliferative and by design cause cellular stress. As in bacteria, this may activate stress-induced mechanisms in tumor cells that allow for adaptation to these therapies. Application of what Rosenberg coined as "anti-evolution" therapies that suppress these stress-induced mechanisms in tumors may dilute or entirely preempt resistance to chemotherapy.
(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)