Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

TRANSCRIPTION REGULATORS SWITCH GENES ON AND OFF
383
a switch that carries out a logic operation in a computer. When lactose is present
AND glucose is absent, the cell executes the appropriate program—in this case,
transcription of the genes that permit the uptake and utilization of lactose.
All transcription regulators, whether they are repressors or activators, must be
bound to DNA to exert their effects. In this way, each regulatory protein acts selectively,
controlling only those genes that bear a cis-regulatory sequence recognized
by it. The logic of the Lac operon first attracted the attention of biologists more
than 50 years ago. The way it works was uncovered by a combination of genetics
and biochemistry, providing some of the first insights into how transcription is
controlled in any organism.
DNA Looping Can Occur During Bacterial Gene Regulation
We have seen that transcription activators help RNA polymerase initiate transcription
and repressors hinder it. However, the two types of proteins are very
similar to one another. For example, to occupy their cis-regulatory sequences,
both the tryptophan repressor and the CAP activator protein must bind a small
molecule; moreover, they both recognize their cis-regulatory sequences using the
same structural motif (the helix–turn–helix shown in Panel 7–1). Indeed, some
proteins (for example, the CAP protein) can act as both a repressor and an activator,
depending on the exact placement of their cis-regulatory sequence relative
to the promoter: for some genes, the CAP cis-regulatory sequence overlaps the
promoter, and CAP binding thereby prevents the assembly of RNA polymerase at
the promoter.
Most bacteria have small, compact genomes, and the cis-regulatory sequences
that control the transcription of a gene are typically located very near to the start
point of transcription. But there are some exceptions to this generalization—
cis-regulatory sequences can be located hundreds and even thousands of nucleotide
pairs from the bacterial genes they control (Figure 7–16). In these cases, the
intervening DNA is looped out, allowing a protein bound at a distant site along
the DNA to contact RNA polymerase. Here, the DNA acts as a tether, enormously
increasing the probability that the proteins will collide, compared with the situation
where one protein is bound to DNA and the other is free in solution. We will
see shortly that, although it is the exception in bacteria, DNA looping occurs in the
regulation of nearly every eukaryotic gene.
A possible explanation for this difference is based on evolutionary considerations.
It has been proposed that the compact, simple genetic switches found
in bacteria evolved in response to large population sizes where competition for
growth put selective pressure on bacteria to maintain small genome sizes. In
contrast, there appears to have been little selective pressure to “streamline” the
genomes of multicellular organisms.
NtrC
bacterial
RNA polymerase
promoter
cis-regulatory
sequence
looped
activation
intermediate
(A) (B) 20 nm
GENE ON
Figure 7–16 Transcriptional activation
at a distance. (A) The NtrC protein is
a bacterial transcription regulator that
activates transcription by directly contacting
RNA polymerase. (B) The interaction of NtrC
and RNA polymerase, with the intervening
DNA looped out, can be seen in the electron
microscope. (B, courtesy of Harrison Echols
and Sydney Kustu.)