27 July

New insights into maintaining epigenetic information during DNA repair

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Researchers from the group of Francesca Mattiroli, in collaboration with Hugo van Ingen at Utrecht University and researchers from various other institutes have discovered a new way in which histones, the proteins around which DNA is wrapped and that contain critical information on how to read the DNA, are handled when damaged DNA is repaired. The DNA repair factor APLF turns out to be able to bind and temporarily store the complete histone complex at once, thereby preserving the information on how the DNA is read, while the DNA is repaired. These results were published in the scientific journal Science Advances on the 27th of July.

To fit the nearly 2 meters of DNA that each of our cells contain into the cell nucleus, which has a size of only a few thousandths of a millimeter, DNA is wrapped tightly around histonesProteins in the nucleus around which the DNA is wound. This way, all the DNA fits inside the nucleus. Through modifications of the histones, the DNA is wound tighter or looser, which changes the accessibility of the genes in that area. Eight histones together form a complex around which the DNA can be wrapped. Histone complexes contain a lot of information on how the surrounding DNA should be read by the cell – should certain genes be active or inactive? This is called epigenetic information. Mistakes in the epigenetic information can cause disease. Therefore, it is important that this information remains intact.

Maintaining epigenetic information

Relatively often, the DNA in our cells is damaged and subsequently repaired. But in order to repair the DNA, the histones first need to be removed. Up until now, it was thought that the histone complex is taken apart in a stepwise manner, and rebuilt after DNA repair, resulting in potential loss of epigenetic information. The current study, done by researchers from the Hubrecht Institute, Utrecht University, the Netherlands Cancer Institute and Leiden University Medical Center, shows however that a certain DNA repair factor, called APLF, can remove the entire histone complex at once from the DNA and place it back after the DNA is repaired, leaving the epigenetic information intact.

It is also remarkable that this is done by a very short region of the APLF protein, which is found in other human proteins as well. Future research will study if these other proteins can also bind the intact histone complex and when they do so. This will help us understand how cells maintain their epigenetic information.

These discoveries change the way researchers look at the preservation of epigenetic information during DNA repair. With this new knowledge, it is possible to study how this process impacts cancer and how we can use it to treat cancer and other developmental diseases. 

 

The tructure of APLF (magenta), bound to the histone complex.
Multidisciplinary collaboration

This study shows the importance of multidisciplinary collaboration. The researchers unraveled this new way of removing and redepositing the histone complex by studying different aspects of the process. First, the group of Hugo van Ingen discovered that APLF bound the intact histone complex and they described its properties. Then, the group of Titia Sixma at the Netherlands Cancer Institute solved the crystal structure of APLF to show its atomic details. Next, Francesca Mattiroli’s group at the Hubrecht Institute found out that the removed histone complexes can be redeposited onto the DNA while keeping the epigenetic information intact, which was confirmed in cells by the group of Haico van Attikum at the Leiden University Medical Center. Mattiroli: “This study shows how fundamental research on how proteins bind together can lead to new ways of thinking about biological processes that are important for human health. It was a team effort, led by Ivan Corbeski and Hugo van Ingen, who recognized the novelty and importance of their early findings and set out to fully understand them by combining many different research expertises.”

 

Publication

Chaperoning of the histone octamer by the acidic domain of DNA repair factor APLF. Ivan Corbeski, Xiaohu Guo, Bruna V. Eckhardt, Domenico Fasci, Wouter Wiegant, Melissa A. Graewert, Kees Vreeken, Hans Wienk, Dmitri I. Svergun, Albert J. R. Heck, Haico van Attikum, Rolf Boelens, Titia K. Sixma, Francesca Mattiroli, Hugo van Ingen. Science Advances 2022

 

 

 

Francesca Mattiroli is group leader at the Hubrecht Institute.