University of California,
Santa Barbara researchers’ discovery of a variation of an enzyme’s ability to
“hop” as it moves along DNA, modifying the genetic material of a
bacteria—and its physical capability and behavior—holds much promise for
biomedical and other scientific applications. Their results are published in the
Journal of Biological Chemistry.
The E. coli bacteria’s adaptive mechanism allows it to change its phenotype—its
observable characteristics—according to its environment. For example, if it
senses a need to find food, to stick to the tissues of its host organism, or to
reproduce, the bacteria will form pili, or hair-like structures, on its
surface, to allow it to move, stick, or pass genetic material.
“We’re trying to
figure out what is it in the cell that’s driving those changes,” said Adam
Pollak, first author of the paper.
The formation of these
pili is driven by an epigenetic mechanism—a “tagging” done by the
enzyme DNA adenine methyltransferase (Dam), which acts on a specific sequence
of DNA, called GATC sites (Guanine-Adenine-Thymine-Cytosine). The tagging signals
the formation of these—appendages a mechanism similar to that in humans, where
tagging directs the formation of tissues for different organs from the same
DNA. This tagging is part of a broader field, called epigenetics, where
modifications made to the genome are heritable and regulate the expression of
Where the prevailing
belief used to be that the enzyme Dam slid down only one side of the bacteria’s
double-helixed DNA looking for these GATC sites, according to the researchers,
Dam can actually “hop” to one or more such sites on both sides of the
“It moves along,
finds a site, and methylates that; but it turns around, reorients itself, and
methylates the other side,” said Norbert Reich, UCSB professor of
chemistry and biochemistry.
Using several strands of
genetically engineered DNA of various lengths and differing distances between
the sites of methylation, the researchers found that the hopping of Dam may
occur more often, depending on the clustering of sites; for example, it is more
likely to occur when two sites are within 10 to 200 base pairs of each other. Clustered
GATC sites are strongly associated with gene regulation, while an isolated GATC
site on the double helix is associated with the copying of DNA. According to
the authors’ findings, the longer the enzyme goes without locating the GATC
sequence of molecules, the less likely that it will undergo this new variation
of hopping, but the introduction of a GATC sequence will stimulate the
mechanism once again.
According to the paper,
hopping can explain the efficiency by which DNA-modifying enzymes can find
their recognition sites, despite the presence of an overwhelming amount of
non-specific DNA; as well as how enzymes can modify more than one site, despite
opposing strand orientations.
The research capitalizes
on decades of observation of E. coli‘s
behavior, and factors that contribute to its virulence, or its ability to
persist and multiply. Studying the mechanisms that switch these abilities on
and off would contribute to how humans can deal with these bacteria, which
exist in warm-blooded creatures, but, in certain instances, can cause diseases.
“If we had
inhibitors that could prevent the switching, we wouldn’t have urinary tract
infections, for instance,” said Pollak.
The same research group
recently reported a similar mechanism in humans, which is disrupted in certain
forms of leukemia.