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Academia Sinica E-news No.358
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Rules are Made to be Broken: Academician Ming-Daw Tsai’s Research Team Uncovers how a Viral DNA Polymerase Breaks the Golden Watson-Crick Rule
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Rules are Made to be Broken: Academician Ming-Daw Tsai’s Research Team Uncovers how a Viral DNA Polymerase Breaks the Golden Watson-Crick Rule

         Replication of DNA occurs in all living organisms and forms the basis of biological inheritance. Replication of DNA famously occurs through the pairing of the nucleic acid (base) building blocks of DNA in a specific pattern, (guanine pairs with cytosine and adenine pairs with thymine). This rule of base pairing is named Watson-Crick base pairing. The synthesis of new strands of DNA is facilitated by enzymes called DNA polymerases. For many years scientists have been fascinated by the fidelity of the DNA polymerase reaction – the way in which the pairing rule is invariably followed. Over the last 10 years, however, polymerases have been discovered that do not follow the Watson-Crick rule of base pairing, and exactly how these enzymes function remains a great wonder to scientists. Recently, a research team led by the director of the Institute of Biological Chemistry, Academician Ming-Daw Tsai has demonstrated the mechanism by which a certain DNA polymerase overcomes Watson-Crick pairing, a discovery of fundamental importance in the understanding of life processes. The research was published in the top chemistry journal, Journal of American Chemical Society (JACS), on March 11, 2014.

         Academician Ming-Daw Tsai and his team studied a DNA polymerase from African Swine Fever Virus named Pol X. Pol X is unusual because it can get guanine (G) to pair with itself, as well as being able to follow conventional Watson-Crick base pairing.

         A DNA polymerase reaction (catalysis) is conventionally considered to proceed first through the binding of the enzyme to DNA, and then the binding of MgdNTP (deoxynucleotide triphosphates, the building blocks for the newly synthesized DNA strands complexed with magnesium). The team found, however, that Pol X is able to bind MgdNTP in the absence of DNA.

         "Kinetic studies suggested that Pol X does not follow the established mechanistic paradigm that DNA polymerases bind DNA before binding to a nucleotide" Tsai explained.

         The research team studied the enzyme in solution by nuclear magnetic resonance (NMR) spectroscopy to determine structures of Pol X in the free, binary (Pol X:MgdGTP), and ternary (Pol X:DNA:MgdGTP with dG:dGTP non-Watson-Crick pairing) forms. The results demonstrate the first solution structural view of DNA polymerase catalysis and a novel mechanism for non-Watson-Crick incorporation by a low-fidelity DNA polymerase.

         The full article entitled "How a low-fidelity DNA polymerase chooses non-Watson-Crick from Watson-Crick incorporation" can be found online at the JACS website at: http://pubs.acs.org/doi/abs/10.1021/ja4102375   The American Society of Biochemistry and Molecular Biology (ASBMB) also reported this story in ASBMB TODAY: http://wildtypes.asbmb.org/2014/03/20/how-a-polymerase-bypasses-the-rules-of-watson-crick-base-pairing/  

         The full list of authors is: Wen-Jin Wu, Mei-I Su, Jian-Li Wu, Sandeep Kumar, Liang-hin Lim, Chun-Wei Eric Wang, Frank H. T. Nelissen, Ming-Chuan Chad Chen, Jurgen F. Doreleijers, Sybren S. Wijmenga, and Ming-Daw Tsai. This research was financially supported by the National Science Council and Academia Sinica.

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