Scientists resolve spatial structure and operating mode
of molecular gene switch in human DNA

Albert Jeltsch, Jacobs Professor of Biochemistry, together with Prof. Xiaodong Cheng, expert in structural biology from Emory University, USA, for the first time successfully resolved the three-dimensional structure of a human enzyme for gene regulation and its operating mode. The study is published in the current online express issue of Nature (doi:10.1038/nature06146).

[ Aug 23, 2007]  The human genom contains 20000-30000 genes as information units. These genes are specifically activated or deactivated by a process called “gene regulation” according to the requirements of the developmental course of a human being. Special proteins, the DNA methyl transferases, play a central role in this process. They are targeted to gene sequences and attach methyl groups as markers to key sites on the DNA, which inhibit the reading and activation of the subsequent gene sequences. Disorders in the gene regulation process potentially lead to developmental defects and might cause diseases.

Using X-ray crystallography Albert Jeltsch and Xiaodong Cheng together with their teams now resolved the spatial structure of the human proteins Dnmt3a and Dnmt3L, which as a DNA methylating functional unit play a central role in the human gene regulation during embryonic development. The structural analysis yielded the surprising result that two Dnmt3a-Dnmt3L units respectively form a dimeric methyltransferase with two active centers with a defined special distance to each other. Functional analyses of the enzyme’s attachment to the target DNA revealed that the specific spatial distance of these active centers quite often match the the spacial distance of the respective DNA key sites in a lock-and-key fashion. Methylation experiments additionally proved the simultaneous activity of the two centers most of the time.

„The special enzymatic structure and working mode of the enzyme we’ve studied indicates a whole new range of aspects in human DNA methylation. The newly discovered enzymatic “pack-of-two” could be a special form of binding-site specificity, for instance. Another possibility would be that the simultaneous action of the two enzymatically active centers indicates that certain crucial gene regulation processes have to be carried out very fast,“ Albert Jeltsch comments on the new findings. „In any case these research results take us closer to an understanding of the highly complex an fascinating process of development from the fertilized egg cell to a complete living organism,“ the Jacobs Scientist adds.