Top and side
view showing the difference in the way that a normal DNA repair glycosylase
enzyme (AAG) and
the new enzyme (AlkD) recognize a damaged DNA base. The AAG enzyme
bends the DNA in
way that forces the damaged base to rotate from its normal position inside the
double helix to
an outside position where the enzyme binds to it and removes it. In contrast,
the AlkD enzyme
senses the chemical features of the damaged base through the DNA backbone,
without
physically contacting the damaged base itself. The enzymes are shown in grey,
the DNA
backbone is
orange, normal DNA base pairs are yellow, the damaged base is purple and its
pair
base is green.
(Brandt Eichman / Vanderbilt)
(October 30, 2015) This
year’s Nobel Prize in chemistry was given to three scientists who each focused
on one piece of the DNA repair puzzle. Now a new study, reported online Oct. 28
in the journal Nature, reports the discovery of a new class of DNA repair
enzyme.
When the structure of DNA was first discovered, scientists
imagined it to be extremely chemically stable, which allowed it to act as a
blueprint for passing the basic traits of parents along to their offspring.
Although this view has remained prevalent among the public, biologists have
since learned that the double helix is in fact a highly reactive molecule that
is constantly being damaged and that cells must make unceasing repair efforts
to protect the genetic information that it contains.
“It’s a double-edged sword,” said Brandt Eichman, associate
professor of biological sciences and biochemistry at Vanderbilt University, who
headed the research team that made the new discovery. “If DNA were too reactive
then it wouldn’t be capable of storing genetic information. But, if it were too
stable, then it wouldn’t allow organisms to evolve.”
The DNA double-helix has a spiral staircase structure with
the outer edges made from sugar and phosphate molecules joined by stair steps
composed of pairs of four nucleotide bases (adenine, cytosine, guanine and
thymine) that serve as the basic letters in the genetic code.
There are two basic sources of DNA damage or lesions:
environmental sources including ultraviolet light, toxic chemicals and ionizing
radiation and internal sources, including a number of the cell’s own
metabolites (the chemicals it produces during normal metabolism), reactive
oxygen species and even water.
The new type of
DNA repair enzyme, AlkD on the left, can identify and remove a damaged DNA base
without forcing
it to physically "flip" to the outside of the DNA backbone, which is
how all the other
DNA repair
enzymes in its family work, as illustrated by the human AAG enzyme on the
right. The
enzymes are
shown in grey, the DNA backbone is orange, normal DNA base pairs are yellow,
the
damaged base is blue and its pair base is green.
(Brandt Eichman / Vanderbilt)
“More than 10,000 DNA damage events occur each day in every
cell in the human body that must be repaired for DNA to function properly,”
said first author Elwood Mullins, a postdoctoral research associate in the
Eichman lab.
The newly discovered DNA repair enzyme is a DNA glycosylase,
a family of enzymes discovered by Tomas Lindahl, who received this year’s Nobel
prize for recognizing that these enzymes removed damaged DNA bases through a
process called base-excision repair. It was the first of about 10 different DNA
repair pathways that biologists have identified to date.