3-D Structure of this image using Jmol
(DNA) is the primary chemical component of chromosomes
and is the material of which genes are made. It is sometimes called
the "molecule of heredity," because parents transmit copied portions
of their own DNA to offspring during reproduction, and because they
propagate their traits by doing so.
and other simple or prokaryotic cell organisms, DNA is distributed
more or less throughout the cell. In the complex or eukaryotic cells
that make up plants, animals and in other multi-celled organisms,
most of the DNA resides in the cell nucleus. The energy-generating
organelles known as chloroplasts and mitochondria also carry DNA,
as do many viruses.
called "the molecule of heredity," pieces of DNA as people typically
think of them are not single molecules. Rather, they are pairs of
molecules, which entwine like vines to form a double helix
(top half of the illustration at the right).
molecule is a strand of DNA: a chemically linked chain of nucleotides,
each of which consists of a sugar, a phosphate and one of four kinds
of aromatic "bases". Because DNA strands are composed of these nucleotide
subunits, they are polymers.
of the bases means that there are four kinds of nucleotides, which
are commonly referred to by the identity of their bases. These are
adenine (A), thymine (T), cytosine (C), and guanine (G).
In a DNA double
helix, two polynucleotide strands come together through complementary
pairing of the bases, which occurs by hydrogen
bonding. Each base forms hydrogen bonds readily to only one
other -- A to T and C to G -- so that the identity of the base on
one strand dictates what base must face it on the opposing strand.
Thus the entire nucleotide sequence of each strand is complementary
to that of the other, and when separated, each may act as a template
with which to replicate the other (middle and lower half of the
illustration at the right).
causes the nucleotide bases to face the helical axis, the sugar
and phosphate groups of the nucleotides run along the outside, and
the two chains they form are sometimes called the "backbones"
of the helix. In fact, it is chemical bonds between the phosphates
and the sugars that link one nucleotide to the next in the DNA strand.
Within a gene,
the sequence of nucleotides along a DNA strand defines a protein,
which an organism is liable to manufacture or "express" at one or
several points in its life using the information of the sequence.
The relationship between the nucleotide sequence and the amino-acid
sequence of the protein is determined by simple cellular rules of
translation, known collectively as the genetic code. Reading along
the "protein-coding" sequence of a gene, each successive sequence
of three nucleotides (called a codon) specifies or "encodes" one
In many species
of organism, only a small fraction of the total sequence of the
genome appears to encode protein. The function of the rest is a
matter of speculation. It is known that certain nucleotide sequences
specify affinity for DNA binding proteins, which play a wide variety
of vital roles, in particular through control of replication and
transcription. These sequences are frequently called regulatory
sequences, and researchers assume that so far they have identified
only a tiny fraction of the total that exist. "Junk DNA" represents
sequences that do not yet appear to contain genes or to have a function.
determines a DNA segment's susceptibility to cleavage by restriction
enzymes, the quintessential tools of genetic engineering. The position
of cleavage sites throughout an individual's genome determines one
kind of an individual's "DNA fingerprint".
bonds between the strands of the double helix are weak enough that
they can be easily separated by enzymes. Enzymes known as helicases
unwind the strands to facilitate the advance of sequence-reading
enzymes such as DNA polymerase. The unwinding requires that helicases
chemically cleave the phosphate backbone of one of the strands so
that it can swivel around the other. The stands can also be separated
by gentle heating, as used in PCR, provided they have fewer than
about 10,000 base pairs (10 kilobase pairs, or
10 kbp). The intertwining of the DNA strands makes long segments
difficult to separate.
When the ends
of a piece of double-helical DNA are joined so that it forms a circle,
as in plasmid DNA, the strands are topologically knotted. This means
they cannot be separated by gentle heating or by any process that
does not involve breaking a strand. The task of unknotting topologically
linked strands of DNA falls to enzymes known as topoisomerases.
Some of these enzymes unknot circular DNA by cleaving two strands
so that another double-stranded segment can pass through. Unknotting
is required for the replication of circular DNA as well as for various
types of recombination in linear DNA.
Space-filling model of a section of DNA molecule
The DNA helix
can assume one of three slightly different geometries, of which
the "B" form described by James D. Watson and Francis Crick is believed
to predominate in cells. It is 2 nanometers wide and extends 3.4
nanometers per 10 bp of sequence. This is also the approximate length
of sequence in which the helix makes one complete turn about its
axis. This frequency of twist (known as the helical pitch)
depends largely on stacking forces that each base exerts on its
neighbors in the chain.
The narrow breadth
of the double helix makes it impossible to detect by conventional
electron microscopy, except by heavy staining. At the same time,
the DNA found in many cells can be macroscopic in length -- approximately
5 centimeters long for strands in a human chromosome. Consequently,
cells must compact or "package" DNA to carry it within them. This
is one of the functions of the chromosomes, which contain spool-like
proteins known as histones, around which DNA winds.
The B form of the
DNA helix twists 360° per 10.6 bp in the absence of strain. But many
molecular biological processes can induce strain. A DNA segment with
excess or insufficient helical twisting is referred to, respectively,
as positively or negatively "supercoiled". DNA in vivo is typically
negatively supercoiled, which facilitates the unwinding of the double-helix
required for RNA transcription.
The two other
known double-helical forms of DNA, called A and Z, differ modestly
in their geometry and dimensions. The A form appears likely to occur
only in dehydrated samples of DNA, such those used in crystallography
experiments, and possibly in hybrid pairings of DNA and RNA strands.
Segments of DNA that cells have methylated for regulatory purposes
may adopt the Z geometry, in which the strands turn about the helical
axis like a mirror image of the B form.
shape and linkage of nucleotides means that a DNA strand always
has a discernable orientation or directionality. Because of this
directionality, close inspection of a double helix reveals that,
although the nucleotides along one strand are heading one way (e.g.
the "ascending strand") the others are heading the other
(e.g. the "descending strand"). This arrangement of the
strands is called antiparallel.
of chemical nomenclature, people who work with DNA refer to the
asymmetric termini of each strand as the 5' and
3' ends (pronounced "five prime" and "three prime").
DNA workers and enzymes alike always read nucleotide sequences in
the "5' to 3' direction". In a vertically oriented
double helix, the 3' strand is said to be ascending while the 5'
strand is said to be descending.
As a result
of their antiparallel arrangement and the sequence-reading preferences
of enzymes, even if both strands carried identical instead of complementary
sequences, cells could properly translate only one of them. The
other strand a cell can only read backwards. Molecular biologists
call a sequence "sense" if it is translated or
translatable, and they call its complement "antisense".
It follows then, somewhat paradoxically, that the template for transcription
is the antisense strand. The resulting transcript is an
RNA replica of the sense strand and is itself sense.
blur the distinction between sense and antisense, because certain
sequences of their genomes do double duty, encoding one protein
when read 5' to 3' along one strand, and a second protein when read
in the opposite direction along the other strand. As a result, the
genomes of these viruses are unusually compact for the number of
genes they contain, which biologists view as an adaptation. Topologists
like to note that the juxtaposition of the 3' end of one DNA strand
beside the 5' end of the other at both termini of a double-helical
segment makes the arrangement a "crab canon".
In some viruses
DNA appears in a non-helical, single-stranded form. Because many
of the DNA repair mechanisms of cells work only on paired bases,
viruses that carry single-stranded DNA genomes mutate more frequently
than they would otherwise. As a result, such species may adapt more
rapidly to avoid extinction. The result would not be so favorable
in more complicated and more slowly replicating organisms, however,
which may explain why only viruses carry single-stranded DNA. These
viruses presumably also benefit from the lower cost of replicating
one strand versus two.
Working in the
19th century, biochemists initially isolated DNA and RNA (mixed
together) from cell nuclei. They were relatively quick to appreciate
the polymeric nature of their "nucleic acid" isolates, but realized
only later that nucleotides were of two types--one containing ribose
and the other deoxyribose. It was this subsequent discovery that
led to the identification and naming of DNA as a substance distinct
(1844-1895) discovered a substance he called "nuclein" in 1869.
Somewhat later he isolated a pure sample of the material now known
as DNA from the sperm of salmon, and in 1889 his pupil, Richard
Altmann, named it "nucleic acid". This substance was found to exist
only in the chromosomes. Max Delbrück, Nikolai V. Timofeeff-Ressovsky,
and Karl G. Zimmer published results in 1935 suggesting that chromosomes
are very large molecules the structure of which can be changed by
treatment with X-rays, and that by so changing their structure it
was possible to change the heritable characteristics governed by
those chromosomes. (Delbrück and Salvador Luria were awarded the
Nobel Prize in 1969 for their work on the genetic structure of viruses.)
In 1943, Oswald Theodore Avery discovered that traits proper to
the "smooth" form of the Pneumococcus could be transferred
to the "rough" form of the same bacteria merely by making the killed
"smooth" (S) form available to the live "rough" (R) form. Quite
unexpectedly, the living R Pneumococcus bacteria were transformed
into a new strain of the S form, and the transferred S characteristics
turned out to be heritable.
In 1944, the
renowned physicist, Erwin Schrödinger, published a brief book entitled
What is Life?, in which he maintained that chromosomes
contained what he called the "hereditary code-script" of life. He
added: "But the term code-script is, of course, too narrow. The
chromosome structures are at the same time instrumental in bringing
about the development they foreshadow. They are law-code and executive
power -- or, to use another simile, they are architect's plan and
builder's craft -- in one." He conceived of these dual functional
elements as being woven into the molecular structure of chromosomes.
By understanding the exact molecular structure of the chromosomes
one could hope to understand both the "architect's plan" and also
how that plan was carried out through the "builder's craft." Francis
Crick, James Watson, Maurice Wilkins, Seymour Benzer, et al., took
up the physicist's challenge to work out the structure of the chromosomes
and the question of how the segments of the chromosomes that were
conceived to relate to specific traits could possibly do their jobs.
Just how the
presence of specific features in the molecular structure of chromosomes
could produce traits and behaviors in living organisms was unimaginable
at the time. Because chemical dissection of DNA samples always yielded
the same four nucleotides, the chemical composition of DNA appeared
simple, perhaps even uniform. Organisms, on the other hand, are
fantastically complex individually and widely diverse collectively.
Geneticists did not speak of genes as conveyors of "information"
in such words, but if they had, they would not have hesitated to
quantify the amount of information that genes need to convey as
vast. The idea that information might reside in a chemical in the
same way that it exists in text--as a finite alphabet of letters
arranged in a sequence of unlimited length--had not yet been conceived.
It would emerge upon the discovery of DNA's structure, but few researchers
imagined that DNA's structure had much to say about genetics.
In the 1950s,
only a few groups made it their goal to determine the structure
of DNA. These included an American group led by Linus Pauling, and
two groups in Britain. At Cambridge University, Crick and Watson
were building physical models using metal rods and balls, in which
they incorporated the known chemical structures of the nucleotides,
as well as the known position of the linkages joining one nucleotide
to the next along the polymer. At King's College, London, Maurice
Wilkins and Rosalind Franklin were examining x-ray diffraction patterns
of DNA fibers.
A key inspiration
in the work of all of these teams was the discovery in 1948 by Pauling
that many proteins included helical (see alpha helix) shapes. Pauling
had deduced this structure from x-ray patterns. Even in the initial
crude diffraction data from DNA, it was evident that the structure
involved helices. But this insight was only a beginning. There remained
the questions of how many strands came together, whether this number
was the same for every helix, whether the bases pointed toward the
helical axis or away, and ultimately what were the explicit angles
and coordinates of all the bonds and atoms. Such questions motivated
the modeling efforts of Watson and Crick.
In their modeling,
Watson and Crick restricted themselves to what they saw as chemically
and biologically reasonable. Still, the breadth of possibilities
was very wide. A breakthrough occurred in 1952, when Erwin Chargaff
visited Cambridge and inspired Crick with a description of experiments
Chargaff had published in 1947. Chargaff had observed that the proportions
of the four nucleotides vary between one DNA sample and the next,
but that for particular pairs of nucleotides -- adenine and thymine,
guanine and cytosine -- the two nucleotides are always present in
Watson and Crick
had begun to contemplate double helical arrangements, and they saw
that by reversing the directionality of one strand with respect
to the other, they could provide an explanation for Chargaff's puzzling
finding. This explanation was the complementary pairing of the bases,
which also had the effect of ensuring that the distance between
the phosphate chains did not vary along a sequence. Watson and Crick
were able to discern that this distance was constant and to measure
its exact value of 2 nanometers from an X-ray pattern obtained by
Franklin. The same pattern also gave them the 3.4 nanometer-per-10
bp "pitch" of the helix. The pair quickly converged upon a model,
which they announced before Franklin herself published any of her
The great assistance
Watson and Crick derived from Franklin's data has become a subject
of controversy, and it has angered people who believe Franklin has
not received the credit due to her. The most controversial aspect
is that Franklin's critical X-ray pattern was shown to Watson and
Crick without Franklin's knowledge or permission. Wilkins showed
it to them at his lab while Franklin was away.
Watson and Crick's
model attracted great interest immediately upon its presentation.
Arriving at their conclusion on February 21, 1953, Watson and Crick
made their first announcement on February 28. Their paper 'A Structure
for Deoxyribose Nucleic Acid' was published on April 25. In an influential
presentation in 1957, Crick laid out the "Central Dogma", which
foretold the relationship between DNA, RNA, and proteins, and articulated
the "sequence hypothesis." A critical confirmation of the replication
mechanism that was implied by the double-helical structure followed
in 1958 in the form of the Meselson-Stahl experiment. Work by Crick
and coworkers deciphered the genetic code not long afterward. These
findings represent the birth of molecular biology.
and Wilkins were awarded a Nobel Prize in 1962, by which time Franklin