As evidence about methylation of DNA accumulated, Arthur Riggs and Abaron Razin17,35 recognized that this modification offered a logically attractive explanation for control of gene expression, but experimental support for that idea remained elusive. They realized from structural studies performed during the 1970s that the conversion of cytosine to 5mC placed a methyl group in an exposed position in the major groove of the DNA helix. And while methyl groups in this position would not affect base pairing, and hence would not impede DNA replication, studies of several proteins such as the lac repressor, histones, and hormone receptors had demonstrated that changes in the major groove affected binding of DNA to proteins. Razin and Riggs concluded that 5mC could profoundly affect the binding of proteins to DNA and they suggested that methylated cytosines would modify protein-DNA interactions and could bring about long-term silencing of gene expression. However, the detailed nature of these interactions was not clear and further developments were needed to complete the picture.
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