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A Genetic Switch: Gene Control and Phage Lambda
"A Genetic Switch" is an introduction to gene function - specifically the genetic repressor. Understanding the repressor function is essential to an understanding of biochemical activity within the gene as it is fundamental to the process by which growth and development are regulated at the molecular level. The book is intended as a basic introduction to repressor function for both advanced and undergraduate and graduate level courses in genetics and biochemistry. It will also be essential reading for researchers and students of phage, viral and general genetics.
- GenresScienceBiologyNonfiction
Paperback
First published April 1, 1986
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Displaying 1 - 3 of 3 reviews
August 15, 2021
Phage lambda is a fascinating biphasic molecular system. In its lysogenic form, lambda exists as prophage: a strand of DNA embedded in E. coli's circular chromosome. But when exposed to an environmental shock (e.g. UV radiation), lambda transitions to lytic phase. The prophage excises itself from E. coli's DNA, replicates, and transcribes several genes that are translated into coat proteins that form viral particles -- which then burst from the unfortunate host and proceed to infect more bacteria.
How does this switch work? How does an environmental perturbation trigger this very specific and complex change?
A Genetic Switch -- while poorly named, since the switch mechanism is better described as "epigenetic" -- is a detailed review of how phage lambda transitions between lysogenic and lytic states.
In living systems (prokaryotes and eukaryotes alike), our environment is constantly influencing gene expression. And insofar as monozygotic twin studies for disease with poor concordance are interesting to you, dissecting a model system like lambda phage helps us understand how one of the more simplistic mechanisms by which environment influences biology works.
Stated differently: if you cloned yourself 100 times, it's highly unlikely that you'd get 100 fungible people. Lambda phage can start to explain why.
----------
Bacteriophages ("phages") are viruses that infect bacteria.
Lambda phage is a type of phage that infects E. coli, a type of bacteria commonly used in the laboratory setting.
Lambda phage looks like the pictures of viruses that you've seen, with the gem-like head filled with DNA and the spidery legs beneath. Lambda phage finds its host, and injects a strand of DNA from its head into the cytosol.
This DNA integrates to a specific site in E. coli's chromosome and sits dormant.
When environmental signals suggest the host is under streess (triggered by things like UV radiation), the phage switches to lytic mode and replicates and lyses the cell. How does this happen?
Ptaschne begins by describing the crucial operator site that determines our phage's fate. It looks something like this:
== < cl gene < ==|OR3|==|OR2|==|OR1|== > cro gene > ==
cl gene - encodes lambda Repressor (hereafter, "Repressor"). Transcribed right to left.
cro gene - encodes Cro, transcribed left to right.
OR1/2/3 - operator sites where protein can bind DNA to regulate expression.
In lysogenic phase, cl but not cro is expressed. When cro is expessed, lytic phase is initiated.
We are going to skip some of the details, but assume that after integration you have some baseline level Repressor that's been expressed. Repressor binds OR site 1 most strongly, followed by 2, followed by 3. Loosely: as [repressor] increases, OR1 is likely to be occupied at the lowest concentrations, followed by OR2, with OR3 occupied only once there are ~100+ free Repressor proteins* floating around in the cytosol.
(*actually this is probably wrong and we don't really know, it's one thing to measure delta G in vitro but quite another to say a damn thing about what's happening in vivo thinking about DNA coiling, unforeseen protein-protein interactions, enzyme localization, and rates of diffusion through a very crowded cell)
When Repressor is bound to OR1 it silences cro. Makes sense: presence of Cro triggers the entry of lytic phase. In practice there is a cooperative binding effect such that Repressor on OR1 increases the affinity of Repressor for OR2 (they behave like .. a switch!) and OR2 binding stabilizes RNA polymerase on a R -> L promoter and allows for more cl expression and thus makes more Repressor.
The magic of binding affinities tells us that when [Repressor] gets high enough, it becomes likely that OR3 will become occupied. Thus, at a high [Repressor], you shut down cl transcription while preventing entry of the lytic phase. Pretty cool!
What happens when a lysogen gets blasted with UV?
- E. coli will begin to express RecA, involved in various DNA repair mechanisms.
- RecA cleaves Repressor in a way that deactivates it (BLUF is that Repressor is actually a dimer in vivo and you block the dimerization by snipping it in two)
- Eventually Repressor concentrations fall and OR2 and OR1 become less and less likely to be occupied
- With OR1 unoccupied, RNA polymerase eventually slips in to a L -> R promoter and transcribes cro, which initiates the lytic cascade
The book goes into great detail on the relevant structural biology, as well as some of the experiments that were used to suss apart the switch mechanism.
----------
Cool story, why do we care about this?
Well, our own cells contain their own "switches" around what we call homeotic genes. Something tells us to begin a pattern of gene expression that makes a cell a liver cell versus a neuron versus some other tissue. Perhaps some of these mechanisms were originally evolved in viruses similar to lambda phage.
On another level, one of the great mysteries of living systems is how environmental stimuli are translated to very specific molecular results. Why does one monozygotic twin end up with T1D and one twin not? (Concordance in type 1 diabetes is 22.8-31.8%) That's vanishingly low! Somewhere along the way an important environmental exposure is causing changes in biology. And if we can begin to pick this apart mechanistically instead of sequencing a bunch of people and getting tissue-level expression data and wishfully gathering all this data in hope it will one day tell us some secrets, that's when we can begin to have much more fine-grained control of our own biology.
How does this switch work? How does an environmental perturbation trigger this very specific and complex change?
A Genetic Switch -- while poorly named, since the switch mechanism is better described as "epigenetic" -- is a detailed review of how phage lambda transitions between lysogenic and lytic states.
In living systems (prokaryotes and eukaryotes alike), our environment is constantly influencing gene expression. And insofar as monozygotic twin studies for disease with poor concordance are interesting to you, dissecting a model system like lambda phage helps us understand how one of the more simplistic mechanisms by which environment influences biology works.
Stated differently: if you cloned yourself 100 times, it's highly unlikely that you'd get 100 fungible people. Lambda phage can start to explain why.
----------
Bacteriophages ("phages") are viruses that infect bacteria.
Lambda phage is a type of phage that infects E. coli, a type of bacteria commonly used in the laboratory setting.
Lambda phage looks like the pictures of viruses that you've seen, with the gem-like head filled with DNA and the spidery legs beneath. Lambda phage finds its host, and injects a strand of DNA from its head into the cytosol.
This DNA integrates to a specific site in E. coli's chromosome and sits dormant.
When environmental signals suggest the host is under streess (triggered by things like UV radiation), the phage switches to lytic mode and replicates and lyses the cell. How does this happen?
Ptaschne begins by describing the crucial operator site that determines our phage's fate. It looks something like this:
== < cl gene < ==|OR3|==|OR2|==|OR1|== > cro gene > ==
cl gene - encodes lambda Repressor (hereafter, "Repressor"). Transcribed right to left.
cro gene - encodes Cro, transcribed left to right.
OR1/2/3 - operator sites where protein can bind DNA to regulate expression.
In lysogenic phase, cl but not cro is expressed. When cro is expessed, lytic phase is initiated.
We are going to skip some of the details, but assume that after integration you have some baseline level Repressor that's been expressed. Repressor binds OR site 1 most strongly, followed by 2, followed by 3. Loosely: as [repressor] increases, OR1 is likely to be occupied at the lowest concentrations, followed by OR2, with OR3 occupied only once there are ~100+ free Repressor proteins* floating around in the cytosol.
(*actually this is probably wrong and we don't really know, it's one thing to measure delta G in vitro but quite another to say a damn thing about what's happening in vivo thinking about DNA coiling, unforeseen protein-protein interactions, enzyme localization, and rates of diffusion through a very crowded cell)
When Repressor is bound to OR1 it silences cro. Makes sense: presence of Cro triggers the entry of lytic phase. In practice there is a cooperative binding effect such that Repressor on OR1 increases the affinity of Repressor for OR2 (they behave like .. a switch!) and OR2 binding stabilizes RNA polymerase on a R -> L promoter and allows for more cl expression and thus makes more Repressor.
The magic of binding affinities tells us that when [Repressor] gets high enough, it becomes likely that OR3 will become occupied. Thus, at a high [Repressor], you shut down cl transcription while preventing entry of the lytic phase. Pretty cool!
What happens when a lysogen gets blasted with UV?
- E. coli will begin to express RecA, involved in various DNA repair mechanisms.
- RecA cleaves Repressor in a way that deactivates it (BLUF is that Repressor is actually a dimer in vivo and you block the dimerization by snipping it in two)
- Eventually Repressor concentrations fall and OR2 and OR1 become less and less likely to be occupied
- With OR1 unoccupied, RNA polymerase eventually slips in to a L -> R promoter and transcribes cro, which initiates the lytic cascade
The book goes into great detail on the relevant structural biology, as well as some of the experiments that were used to suss apart the switch mechanism.
----------
Cool story, why do we care about this?
Well, our own cells contain their own "switches" around what we call homeotic genes. Something tells us to begin a pattern of gene expression that makes a cell a liver cell versus a neuron versus some other tissue. Perhaps some of these mechanisms were originally evolved in viruses similar to lambda phage.
On another level, one of the great mysteries of living systems is how environmental stimuli are translated to very specific molecular results. Why does one monozygotic twin end up with T1D and one twin not? (Concordance in type 1 diabetes is 22.8-31.8%) That's vanishingly low! Somewhere along the way an important environmental exposure is causing changes in biology. And if we can begin to pick this apart mechanistically instead of sequencing a bunch of people and getting tissue-level expression data and wishfully gathering all this data in hope it will one day tell us some secrets, that's when we can begin to have much more fine-grained control of our own biology.
August 4, 2012
An excellent overview of the principles of molecular biology with lots of great illustrations that add immensely to the book. More geared towards the undergraduate science student than to the layman, but probably accessible to a dedicated layman as well.
November 3, 2010
Classic and brilliant text on gene regulation. Easy enough for the layperson, deep enough for the molecular biologist. Plus it's only 100 pages. I definitely learned some new things from this.
Displaying 1 - 3 of 3 reviews