Scientists have found that six polymer alternatives to DNA
can pass on genetic information, and have evolved one type to
specifically bind target molecules.
1 They say that their work
reveals both broader chemical possibilities for these key life
functions and provides a powerful tool for nanotechnology and
medicine.
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HNA could just as easily have been the molecule of life
as DNA it now seems © Science/AAAS
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'There
is no overwhelming functional imperative for life to be based on DNA or
RNA,' says Phil Holliger from the MRC Laboratory of Molecular Biology
in Cambridge, UK, who led the team. 'Other polymers can perform these
functions, at least at a basic level.' Holliger's team's xeno-nucleic
acid (XNA) polymers each replace DNA's ribofuranose sugar ring with six
other cyclic structures that can still form helical chains and base
pairings. But rather than using relatively inefficient chemical
synthesis, the scientists wanted to exploit polymerase and reverse
transcriptase enzymes to copy genetic information from DNA templates to
XNAs. In living organisms, polymerases can make RNA from nucleotide
monomers using existing DNA strands as templates. Reverse transcriptases
can then create a copy of the original DNA strand from that RNA in the
same way.Yet those processes don't normally work with the kind
of unnatural nucleotides the team used. Consequently, MRC scientist
Vitor Pinheiro first mutated and then selected polymerase enzymes that
best processed 1,5-anhydrohexitol nucleic acid (HNA) and cyclohexenyl
nucleic acid (CeNA) nucleotide trisphosphates. As well as isolating an
enzyme that would make long enough polymers with all six XNA types to
encode genetic information, he similarly engineered reverse
transcriptases. Together the enzymes could accurately replicate genetic
information from DNA to XNA and back, but with enough copying mistakes
for functions to evolve. 'For the best ones it's 99% accurate or
better,' Holliger tells
Chemistry World. 'You really don't need more than that.'
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Xeno-nucleic acids can store genetic information that can be processed into
DNA and back again by mutated polymerases
© Science/AAAS
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Repeated
replication cycles were then used to evolve potent HNA aptamers,
molecules that could act as drugs by recognising and binding to specific
targets. In one example, starting from structures similar to DNA and
RNA aptamers for HIV trans-activating response RNA (TAR), the team
isolated HNAs that might be able to target HIV. These HNAs were then
converted to DNA and back again, selecting for affinity to TAR over
eight rounds of evolution, after which common genetic motifs emerged.
'Aptamers have the potential to rival antibodies in some clinical
settings if we can get the properties right,' Holliger explains. 'This
technology certainly has the potential to do that.' Steven
Benner, director of the Westheimer Institute at the Foundation for
Applied Molecular Evolution in the US, notes that replacing DNA's sugar
ring complements his team's introduction of non-standard nucleotide
bases.
2 'Together, these two classes of artificial chemical
systems capable of heredity and evolution represents an expansion of our
theories relating to the structure of molecules and the phenomenon of
genetics,' he comments. 'It is relevant to biotechnology here on Earth
as well as the possible forms that life might take throughout the
cosmos.'
Jack Szostak, who investigates processes that allowed
early chemical and biological evolution on the Earth at Harvard
University, US, calls Holliger's team's work 'very exciting'. 'This is
very interesting with respect to the origin of life,' he says. 'In
principle, many different polymers could serve the roles of RNA and DNA
in living organisms. Why then does modern biology use only RNA and DNA?
The answer probably lies in two "filters". First, only some nucleic
acids could actually be made on the early Earth. Second, of those
polymers that actually could be made, some may have been functionally
superior to others in terms of ease or accuracy of replication, or
ability to generate catalytic folded structures.'
