Crystalizing cell memory – University of Copenhagen

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06 July 2015

Crystalizing cell memory

Cell memory

Researchers from the University of Copenhagen have been digging into the bio-physical basis of cellular memory. Based on tiny crystals of interacting molecules, they have disclosed how a single protein operates both to copy our DNA and enable cells to remember their cell-type specific functions when they divide. The results are published in Nature Structural and Molecular Biology.

-The cells of our body all contain the same genetic information, yet they manifest specialized tissue specific functions, which need to be maintained throughout life. This is key for normal development, proper body function and to avoid disease. We now reveal how a molecule central for copying DNA also pass on cell-type specific memory to new generations of cells, explains group leader Anja Groth, who has headed the research team.

Crystals reveal memory-preserving functions

The researchers have collaborated with the Patel laboratory at the Memorial Sloan Kettering Cancer Center (New York) to obtain a crystal structure of a DNA copying enzyme, MCM2, bound to special histone proteins. The histones organise our DNA into an ordered architecture and orchestrate that cell-type relevant genes are active and irrelevant genes are silent, thereby supplying our cells with a memory of their identity.

-Obtaining a crystal structure of these molecules provides us with a snapshot of how cells can transfer tissue-specific information in histones to daughter cells. What we show is that MCM2 together with the protein ASF1 function as essential memory-preserving machines by transferring histones to the DNA of the daughter cells. By understanding how these molecules physically interact, we have identified a mode by which cellular memory is maintained, says PhD student Caroline Strømme, who has headed the experiments in the Groth lab.

Detailed molecular understanding sheds light on cancer

Anja Groth’s group has its basis in molecular cell biology, however to solve the big questions in biology, they are reaching out to other disciplines. For the current study, involvement of a top international protein crystallography group has been crucial and the Groth group also engages in multiple other interdisciplinary collaborations.

-Understanding how biology works even down to the atomic level is important to understand life, and importantly, this level of details can directly provide us with handles to tackle malfunctions in disease. Understanding how cellular memory is maintained is key to understand cancer, where the cells upon forgetting their normal identity acquire undesired and dangerous properties, says Anja Groth.

Now, the researchers would like to gain a deeper insight into how MCM2 maintains tissue-specific cell functions through its dual role in DNA copying and management of histones. Their goal is to understand how the processes normally work, but will in time also elucidate what can go wrong in cancer and give clues to how the wrong turns can be corrected through cancer treatment.

Anja Groth is an EMBO Young Investigator and her research is supported by the Danish National Research Foundation to the Center for Epigenetics (DNRF82), European Commission ITN FP7 'aDDRess’ and an ERC Starting Grant (ERC2011StG, no. 281,765), the Danish Cancer Society, the Danish Medical Research Foundation and the Lundbeck Foundation.