Molecular biology: DNA packaging supports cell division

The genetic molecule DNA is present in the cell nucleus as a densely packed complex of DNA and proteins called chromatin. The genetic material is wrapped in sections around a core of special proteins, the histones, and forms so-called nucleosomes, which are arranged along the DNA like pearls on a string. For one of the fundamental processes of life, replication, the duplication of DNA, this literally „tangled“ structure was, according to previous textbook knowledge, more of a barrier that had to be loosened and overcome with energy expenditure. A team led by molecular biologist Dr Christoph F. Kurat from the Biomedical Centre of LMU (BMC) has now shown that this is not the whole truth: at certain points in the genome, the starting points of replication, a characteristic nucleosome structure is crucial for replication to start at all, as the researchers report in the journal Nature.

Before a cell can divide, it must duplicate its genetic material. This process does not just take place at one point, but the molecular machines of replication start simultaneously at many replication start points along the chromosomes. Human cells have 30,000 of these so-called origins („replication origins“), and in the unicellular Bäcker yeast with a smaller genome, which Kurat's team investigated as a model organism, there are still around 400. Some time ago, researchers found characteristic chromatin structures in these origins: the nucleosomes are arranged very regularly at these sites, „much more orderly than in the rest of the genome“, says Kurat.

Minimalistic replication in a test tube
In order to investigate how this regularity of structure comes about and how it affects replication, Kurat and his team spent many years isolating the proteins and origins involved in replication from yeast cells so that they could recreate a functional replication system in a test tube. „Such a biochemical reconstitution approach is extremely complex“, emphasises Kurat, „but also very valuable for understanding complicated processes in detail. One stroke of luck for us was the very fruitful collaboration with colleagues at the BMC and the MPI of Biochemistry.“

With these reconstitutions, the researchers were able to demonstrate which factors generate the regular chromatin structure at the origins and how important this is for the replication machinery to get going at its starting points. „Mutant cells without this chromatin structure are not viable“, says Erika Chacin, the first author of the study. A key factor for the start of replication is the protein complex ORC (Origin Recognition Complex), which has long been known to recruit the necessary parts of the replication machinery. To their surprise, the scientists discovered that this complex has a second function: It is crucially involved in the formation of the ordered chromatin structure at the origins by arranging the nucleosomes accordingly together with so-called chromatin remodeler complexes.

„Our results help to better understand replication“, says Kurat. This is one of the very basic processes of life and a deeper understanding of it is important in itself. In addition, both replication and chromatin structures get out of hand in cancer cells, for example. The fact that we are now bringing both aspects together could help us to develop better drugs in the future. Many cancer drugs inhibit DNA replication. This is associated with severe side effects. The chromatin structure could be a new lever that could be used in the future.

Article from 05/04/2023, idw