Augmenting the alphabet-Genetic code

Rcjohnsen rcjohnsen at
Sun Sep 3 16:16:57 EST 2000

Wednesday 30 August 2000  NATURE
chemistry : Augmenting the alphabet


The French writer Georges Perec once wrote an entire novel without using the
letter 'e'. Communicating with a restricted alphabet must be a frustrating
business. Yet the genetic messages of the cell get by with just four
characters, encoded in the four varieties of small molecule, called 'bases',
that constitute DNA. 
Now a team of US chemists has come up with a way to broaden the genetic
alphabet, creating the potential to write molecular messages in a language
quite alien to normal cells. This work is reported in the Journal of the
American Chemical Society1.
The four DNA bases are adenine, thymine, cytosine and guanine, denoted A, T, C
and G. These recur in specific sequences along the backbone of DNA's coiled
double helix, making up a code that tells the cell how to put together the
protein molecules that it needs in order to function. 
Protein molecules have complex structures built up from 20 components; but
these can be translated from the four-character genetic code because the DNA
bases are read in groups of three, with 64 permutations.
Nevertheless, researchers have many reasons to be interested in creating a new
genetic code with different characters. For example, DNA with non-natural bases
might be more resistant to chemical degradation than natural DNA. Or
non-natural 'genes' inserted into the genome might influence the way that
natural genes are translated into proteins.
Conventional bases combine in pairs that zip together the twin strands of the
double helix. Their stickiness comes from a kind of interaction called a
hydrogen bond, and is highly selective: A sticks only to T, and C to G.
Previously, researchers have tried to introduce new hydrogen-bonding bases into
DNA, but have been hampered by the bases' tendency to stick together less
Floyd Romesberg and colleagues at the Scripps Research Institute in La Jolla,
California, have taken a different approach. They have incorporated into DNA a
base pair that unites instead via 'hydrophobic' interactions. Unlike
conventional DNA bases, the new variety are relatively insoluble in water, and
so they tend to attract one another and clump together rather as grease
globules coalesce in water. This has the advantage that the artificial bases
have virtually no inclination to pair up with the natural, hydrogen-bonding
Romesberg and colleagues have shown previously that one particular pair of
synthetic bases, denoted '7AI' and 'ICS', pair up efficiently when attached to
the backbone of the double helix. But to truly function as DNA bases, such
artificial constructs must be able to interact with the protein enzymes that
process DNA in the cell. Most importantly, they must be accepted as respectable
components of DNA by the enzyme that puts the double helix together, called
'DNA polymerase'. If the enzyme decides that the new bases are acceptable, the
mutated version of DNA with a broader character set could be constructed and
copied at will.
Both 7AI and ICS are tolerated as building blocks by a particular kind of
bacterial DNA polymerase. But they are far from ideal. Each has a strong
propensity to pair up with another copy of itself, forming 7AI:7AI and ICS:ICS
unions as well as the desired 7AI:ICS pair. Romesberg and colleagues have now
found a way to avoid these 'mismatches' by using modified versions of the two
artificial bases.
They synthesized a whole range of variants and trawled through them to find
versions that would pair up selectively. The search produced a non-natural pair
that DNA polymerase would incorporate into a growing DNA double helix
efficiently and selectively. This makes the new pairing, denoted PP:MICS, the
first addition to the genetic code that allows new genetic 'words' to be
written without too many mistakes. 


1.	Wu, Y. et al. Efforts towards expansion of the genetic alphabet:
optimization of interbase hydrophobic interactions. Journal of the American
Chemical Society 122, 7621-7632 (2000).

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