Precision work prior to cell division: how enzymes optimize DNA structure

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Before a cell can divide, it has to precisely duplicate its entire genetic information. However, the DNA in the cell exists as part of a DNA-protein complex known as chromatin. For this purpose, the DNA is wrapped around a core of histone proteins and tightly packed into so-called nucleosomes. So that the genetic material can be reliably copied, the chromatin has to be temporarily reorganized in certain places and adopt a very specific architecture. A team led by molecular biologists Professor Axel Imhof and Professor Christoph Kurat at the Biomedical Center (BMC) has now deciphered how the precise packaging of DNA is controlled at the beginning of cell division.

In previous studies, Kurat and his team had already demonstrated that the so-called origin recognition complex (ORC) plays a key role as regulator of the chromatin structure. This complex coordinates various molecular assistants, including the chromatin remodeler INO80.

These molecules ensure that the correct structure is achieved at the starting points of DNA replication – the so-called origins: It is precisely here that a piece of DNA has to be exposed and flanked by regularly spaced nucleosome arrays. This particular arrangement is essential, as the cellular replication machinery can only begin copying the genetic material when the DNA is correctly organized here.

Phosphorylation functions as molecular switch

In their latest study, the researchers investigated the critical question as to how this chromatin organization is temporally coordinated with the cell cycle. They focused particularly on the enzyme DDK (Dbf4-Dependent Kinase), which was chiefly known for its direct activation of the central replication machinery. By means of a comprehensive proteomic analysis, the researchers demonstrated that the chromatin remodeler INO80 is also a key target of DDK. The enzyme is a so-called kinase, meaning it chemically modifies its target molecules by transferring phosphate groups to them. This phosphorylation functions like a molecular switch, as it alters the internal structure of INO80 and increases its activity.

Without this modification, INO80 cannot position the nucleosomes precisely enough at the replication origins. And so it is ensured that INO80 becomes “replication competent” at exactly the right moment. Cells that lack this phosphorylation exhibit clear delays in starting replication and respond extremely sensitively to replication stress.

“Our findings show that cell cycle kinases, beyond the tasks they perform for the central replication machinery, also prepare the ‘landscape’ in which these machines operate,” explain Imhof and Kurat. “This makes it increasingly clear that nucleosomes are not just obstacles to replication, but also play a decisive role in controlling important processes.”

P. Bansal et al.: Dbf4-Dependent Kinase Finetunes INO80 Function at Chromosome Replication Origins. Nature Communications 2026