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Posted: Jun 4th, 2012 Study suggests expanding the genetic alphabet may be easier thanpreviously thought ( Nanowerk News ) A new study led by scientists at The Scripps Research Institutesuggests that the replication process for DNA he geneticinstructions for living organisms that is composed of four bases(C, G, A and T) s more open to unnatural letters than hadpreviously been thought. An expanded "DNA alphabet" could carrymore information than natural DNA, potentially coding for a muchwider range of molecules and enabling a variety of powerfulapplications, from precise molecular probes and nanomachines touseful new life forms. The new study, which appears in the June 3, 2012 issue of Nature Chemical Biology ( "KlenTaq polymerase replicates unnatural base pairs byinducing a Watson-Crick geometry" ), solves the mystery of how a previously identified pair ofartificial DNA bases can go through the DNA replication processalmost as efficiently as the four natural bases. "We now know that the efficient replication of our unnatural basepair isn't a fluke, and also that the replication process is moreflexible than had been assumed," said Floyd E. Romesberg, associateprofessor at Scripps Research, principal developer of the new DNAbases, and a senior author of the new study. The Romesberglaboratory collaborated on the new study with the laboratory ofco-senior author Andreas Marx at the University of Konstanz inGermany, and the laboratory of Tammy J. Dwyer at the University ofSan Diego. Adding to the DNA Alphabet Romesberg and his lab have been trying to find a way to extend theDNA alphabet since the late 1990s. In 2008, they developed theefficiently replicating bases NaM and 5SICS, which come together asa complementary base pair within the DNA helix, much as, in normalDNA, the base adenine (A) pairs with thymine (T), and cytosine (C)pairs with guanine (G). The following year, Romesberg and colleagues showed that NaM and5SICS could be efficiently transcribed into RNA in the lab dish.But these bases' success in mimicking the functionality of naturalbases was a bit mysterious. They had been found simply by screeningthousands of synthetic nucleotide-like molecules for the ones thatwere replicated most efficiently. And it had been clear immediatelythat their chemical structures lack the ability to form thehydrogen bonds that join natural base pairs in DNA. Such bonds hadbeen thought to be an absolute requirement for successful DNAreplication process in which a large enzyme, DNA polymerase,moves along a single, unwrapped DNA strand and stitches togetherthe opposing strand, one complementary base at a time. An early structural study of a very similar base pair indouble-helix DNA added to Romesberg's concerns. The data stronglysuggested that NaM and 5SICS do not even approximate theedge-to-edge geometry of natural base pairs ermed the Watson-Crickgeometry, after the co-discoverers of the DNA double-helix.Instead, they join in a looser, overlapping, "intercalated"fashion. "Their pairing resembles a 'mispair,' such as twoidentical bases together, which normally wouldn't be recognized asa valid base pair by the DNA polymerase," said Denis Malyshev, agraduate student in Romesberg's lab who was lead author along withKarin Betz of Marx's lab. Yet in test after test, the NaM-5SICS pair was efficientlyreplicable. "We wondered whether we were somehow tricking the DNApolymerase into recognizing it," said Romesberg. "I didn't want topursue the development of applications until we had a clearerpicture of what was going on during replication." Edge to Edge To get that clearer picture, Romesberg and his lab turned toDwyer's and Marx's laboratories, which have expertise in findingthe atomic structures of DNA in complex with DNA polymerase. Theirstructural data showed plainly that the NaM-5SICS pair maintain anabnormal, intercalated structure within double-helix DNA utremarkably adopt the normal, edge-to-edge, "Watson-Crick"positioning when gripped by the polymerase during the crucialmoments of DNA replication. "The DNA polymerase apparently induces this unnatural base pair toform a structure that's virtually indistinguishable from that of anatural base pair," said Malyshev. NaM and 5SICS, lacking hydrogen bonds, are held together in the DNAdouble-helix by "hydrophobic" forces, which cause certain molecularstructures (like those found in oil) to be repelled by watermolecules, and thus to cling together in a watery medium. "It'svery possible that these hydrophobic forces have characteristicsthat enable the flexibility and thus the replicability of theNaM-5SICS base pair," said Romesberg. "Certainly if their aberrantstructure in the double helix were held together by more rigidcovalent bonds, they wouldn't have been able to pop into thecorrect structure during DNA replication." An Arbitrary Choice? The finding suggests that NaM-5SICS and potentially other,hydrophobically bound base pairs could some day be used to extendthe DNA alphabet. It also hints that Evolution's choice of theexisting four-letter DNA alphabet n this planet ay have beensomewhat arbitrary. "It seems that life could have been based onmany other genetic systems," said Romesberg. He and his laboratory colleagues are now trying to optimize thebasic functionality of NaM and 5SICS, and to show that these newbases can work alongside natural bases in the DNA of a living cell. "If we can get this new base pair to replicate with high efficiencyand fidelity in vivo, we'll have a semi-synthetic organism,"Romesberg said. "The things that one could do with that are prettymind blowing.". I am an expert from continuous-castingmachine.com, while we provides the quality product, such as Melting Induction Furnace Manufacturer , Continuous Casting Machine Parts, Billet Casting Machine,and more.
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