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Key Words
genetic circuits, gene modules, developmental pathways, developmental decisions, threshold effects, host factors
Abstract
The lysis-lysogeny decision of bacteriophage lambda (λ) is a paradigm for developmental genetic networks. There are three key features, which characterize the network. First, after infection of the host bacterium, a decision between lytic or lysogenic development is made that is dependent upon environmental signals and the number of infecting phages per cell. Second, the lysogenic prophage state is very stable. Third, the prophage enters lytic development in response to DNA-damaging agents. The CI and Cro regulators define the lysogenic and lytic states, respectively, as a bistable genetic switch. Whereas CI maintains a stable lysogenic state, recent studies indicate that Cro sets the lytic course not by directly blocking CI expression but indirectly by lowering levels of CII which activates cI transcription. We discuss how a relatively simple phage like λ employs a complex genetic network in decision-making processes, providing a challenge for theoretical modeling.
INTRODUCTION
A central challenge in the post genomic era is to understand processes governing the dynamics of highly complex genetic regulatory networks. A growing number of theoretical modeling investigators are attempting to explain the underlying principles of complex regulatory networks involved in normal mammalian development, including alterations that can result in a disease state such as cancer. Analysis of such complex systems would be greatly facilitated by similar studies using an ideal paradigm in which most if not all of the elements composing the system were known. Phage λ, the most comprehensively studied bacteriophage, is the prototype of a class of lambdoid phages with whom it shares similar genome organization and functions (38, 82). Studies of λ that began in the 1950s continue to reveal key molecular processes in gene regulatory mechanisms and development. However, despite years of study, many genetic interactions still remain to be uncovered and those that we already know require reexamination. For an accurate, complete, and quantitative analysis of the genetic network, in particular its temporal progression, these remaining questions need to be addressed. In this review we summarize a systems biology approach to the study of genetic regulatory circuits of phage λ. We define the individual components of the circuits and switches, describe the kinetics of their interactions, and...