Ore.– Oregon State University researchers
have made significant new advances in determining
the structure of all possible DNA sequences – a discovery
that in one sense takes up where Watson and Crick
left off, after outlining in 1953 the double-helical
structure of this biological blueprint for life.
of the fundamental problems
in biochemistry is to
predict the structure
of a molecule from its
sequence – this has been referred to as the "Holy
Grail" of protein chemistry.
scientists have announced in the Proceedings
of the National Academy of Sciences that
they have used X-ray crystallography to determine
the three-dimensional structures of nearly all
the possible sequences of a macromolecule, and
thereby create a map of DNA structure.
work of this type expands,
it should be fundamentally
important in explaining the actual biological function
of genes - in particular, such issues as genetic "expression," DNA
mutation and repair, and why some DNA structures
are inherently prone to damage and mutation. Understanding
DNA structure, the scientists say, is just as necessary
as knowing gene sequence. The human genome project,
with its detailed explanation of the genetic sequence
of the entire human genome, is one side of the coin.
The other side is understanding how the three-dimensional
structure of different types of DNA are defined by
those sequences, and, ultimately, how that defines
"There can be 400 million nucleotides in a human
chromosome, but only about 10 percent of them actually
code for genes," said Pui Shing Ho, professor and
chair of the OSU Department of Biochemistry and Biophysics. "The
other 90 percent of the nucleotides may play different
roles, such as regulating gene expression, and they
often do that through variations in DNA structure."
"Now, for the first time, we're really starting
to see what the genome looks like in three dimensional
reality, not just what the sequence of genes is," Ho
said. "DNA is much more than just a string of letters,
it's an actual structure that we have to explore
if we ever hope to understand biological function.
This is a significant step forward, a milestone in
DNA structural biology."
the early 1950s, two
researchers at Cambridge
University – James Watson and Francis Crick – made
pioneering discoveries by proposing the double-helix
structure of DNA, along with another research group
in England about the same time. They later received
the Nobel Prize for this breakthrough, which has
been called the most important biological work of
the past century and revolutionized the study of
biochemistry. Some of the other early and profoundly
important work in protein chemistry was done by Linus
Pauling, an OSU alumnus and himself the recipient
of two Nobel Prizes.
Watson and Crick actually
identified only one structure
of DNA, called B-DNA,
when in fact there are
many others – one of which was discovered
and another whose structure was solved at OSU in
recent years – that all have different effects on
Aside from the genetic sequence that DNA encodes,
the structure of the DNA itself can have profound
biological effects, scientists now understand. Until
now, there has been no reliable method to identify
DNA structure from sequence, and learn more about
its effects on biological function.
In their studies, the OSU scientists used X-ray
examination of crystalline DNA to reconstruct exactly
what the DNA looks like at the atomic level. By determining
63 of the 64 possible DNA sequences, they were able
to ultimately determine the physical structure of
the underlying DNA for all different types of sequences.
Another important part of this study is the finding
that the process of DNA crystallization does not
distort its structure.
"Essentially, this is a proof of concept, a demonstration
that this approach to studying DNA structure will
work, and can ultimately be used to help understand
biology," Ho said.
instance, one of the
unusual DNA structures
called a Holliday junction, whose structure was co-solved
at OSU about five years ago, apparently plays a key
role in DNA's ability to repair itself – a vital
A more fundamental understanding of DNA structure
and its relationship to genetic sequences, researchers
say, helps set the stage for applied advances in
biology, biomedicine, genetic engineering, nanotechnology
and other fields.
The recent work was supported by grants from the
National Institutes of Health and the National Science
By David Stauth, 541-737-0787
SOURCE: Pui Shing Ho, 541-737-2769
Contact: Pui Shing Ho
Oregon State University