An amazing distortion in DNA induced by a methyltransferase.

Much of my work in biology has been driven by my early training in chemistry. When studying a new chemical compound, the first and most important thing is to determine its detailed molecular structure. For a molecular biologist that usually means determining some DNA sequence, since an accurate knowledge of sequence will then allow the proper design of experiments to examine function. I was first exposed to the idea of macro-molecular sequences while I wa s a postdoctoral fellow with Jack Strominger at Harvard. During that time I briefly visited Fred Sanger's laboratory in Cambridge, England to learn the methodology of RNA fingerprinting and sequencing. Shortly before moving to Cold Spring Harbor Laboratory, I learnt of restriction enzymes from a lecture by Dan Nathans and immediately decided that here was the key to DNA sequencing. The idea was that by mapping restriction sites and sequencing small fragments, longer gene-size sequences could be put together. My laboratory set out to isolate and characterize as many restriction enzymes as possible (Roberts, 1976). We began to use these enzymes to map Adenovirus-2 DNA (Mulder et al., 1974) and to identify small fragments that might be worth sequencing. One such fragment would contain the 5'-end of an Adenovirus-2 mRNA and the eukaryo-tic promoter that controlled its expression. It was the hunt for this promoter containing fragment that led to our discovery of split genes and RNA developed DNA sequencing methods and we f occused our attention on the sequence requirements for RNA splicing. Joe Sambrook, Walter Keller and others cloned the tripartite leader that was present on Adenovirus-2 late mRNAs and Sayeeda Zain determined its sequence (Zain et al., 1979). Soon we undertook the complete sequence of the Adenovirus-2 genome, which was eventually finished as a collaborative effort with Ulf Pettersson's laboratory (Roberts et al., 1986). We realized early on that computational help would be essential for the sequencing project and we developed many programs for assembling and