July 7, 2020 /

New publication in "Nature Communications"

Gene duplication and disease: the downside of specialization

Neue Veröffentlichung in "Nature Communications"

In the course of the evolution of higher organisms such as mammals, gene duplication often occurs. The resulting "twin genes" have a very similar genetic makeup, but are independent of each other and can therefore specialize in certain tasks. An example of this is DNA methylation, a chemical change in the basic building blocks of the genetic material of a cell, which is caused by the transfer of methyl groups by enzymes (DNA methyl transferases, DNMT) to certain locations in the DNA. The DNA-methyltransferases DNMT3A and DNMT3B are two forms of these enzymes in human cells that have arisen from gene duplication.

Over 20 years ago, it was discovered that DNMT3B is essential for the DNA methylation of certain regions in the human genome and that insufficient activity of DNMT3B leads to the so-called ICF syndrome. However, why DNMT3B is specifically required for this task and why, for example, the twin DNMT3A cannot take over this task has so far remained unknown.

DNMT3B is required for the methylation of certain sequences in human chromosomes (orange). The specificity of DNMT3B for these regions is determined by a specific protein loop around Arginine 823 (gray). Figure: University of Stuttgart / IBTB

In cooperation with groups from the University of California and the University of North Carolina at Chapel Hill, our team has now been able to solve the structure of DNMT3B in complex with other DNA sequences and measure the turnover rate of DNA methylation by DNMT3B and DNMT3A on thousands of DNA sequences. It was shown that DNMT3B is particularly active on its target sequences in the human genome due to a special protein loop, while DNMT3A can only work poorly on these sequences.

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