Our bodies are made up of trillions of cells with each cell having a genome in the form of DNA that contains instructions for how a cell should function. This DNA contains 4 important molecules called nitrogen bases – Adenine, Guanine, Cytosine, and Thymine – popularly known as A, G, C and T. The specific sequence of these molecules along a sugar-phosphate backbone determines how and a cell synthesizes proteins and enzymes involved in various cellular activities. Changes to this sequence, called mutations, causes changes in how cells function. This brings about variability and can also cause diseases like cancer.
When DNA replicates, as part of normal cell division and growth, cells ensure that there are no errors while the sequence is being copied. The chemical structure of each of the 4 nitrogen bases only allows copying a certain base opposite to it. For example, A can only pair with T and G can only pair with C. However, as rarely as once in a million bases, replication spontaneously copies the wrong base (say, pairing G with T) causing mutations.
Quantum Jitters enable shape-shifting
A new study by a group of chemists and biochemists has now unravelled a mechanism by which these rare misincorporations can happen within cells. Results from their experiments show that the base G often misincorporates T instead of C. This happens because of a tiny rearrangement in the shape of T that allows it to pair with G. They called these rearrangements quantum jitters as these rearrangements last only for a thousandth of a second. They also discovered that the frequency of these rearrangements depends on the sequence of the DNA. For example, they found that these mistakes were more common in the regions of DNA with a greater number of Gs and Cs than in a region with more As and Ts.
The quantum jitters happen when a thymine molecule briefly shifts shapes into its tautomeric or anionic forms allowing it to incorporate opposite a guanine molecule during DNA replication. Since this rearrangement lasts for only a very small fraction of the time, there is only a small time-frame within which it can be incorporated into the DNA during replication. This explains the rare misincorporations during normal DNA replication. Combined with the sequence specificity of these misincorporations, the scientists propose this mechanism to be a built-in clock that restricts the mutations to be rare.
In their landmark 1953 paper describing the iconic structure of the DNA double helix, Watson and Crick hypothesized that DNA bases might be able to change their shape so that mispairs could pass as the real thing. The current research validates this prediction.
The researchers also speculate that these quantum jitters may be responsible not only for errors in replication, but also in other molecular processes such as transcription, translation, and DNA repair. Therefore, the researchers plan to continue to investigate how these alternative states might disrupt the seamless flow of information contained within our DNA.
- Isaac J. Kimsey et al., Dynamic basis for dG•dT misincorporation via tautomerization and ionization. Nature 25487, Online (2018). doi:10.1038/nature25487.
- Isaac J. Kimsey, Bharathwaj Sathyamoorthy, Katja Petzold, Zachary W. Stein, Hashim M. Al-Hashimi. Visualizing transient Watson–Crick-like mispairs in DNA and RNA duplexes. Nature 519, 315–320 (2015). doi:10.1038/nature14227.