Researchers from the Mattiroli group have found that the way DNA is packaged in cells can directly impact how fast DNA itself is copied during cell division. They discovered that DNA packaging sends signals through an unusual pathway, affecting the cell's ability to divide and grow. This opens up new doors to study how the copying of the DNA and its packaging are linked. These findings, published in Molecular Cell , may help scientists to find therapies and medicines for diseases such as cancer in the future.
Chromatin as a guide
Every day, our cells divide. Each time they need to copy both their DNA and the structure in which the DNA is packed. This packaging, called chromatin, acts as a guide. It tells the cell how, where and when to 'read' and use the information in the DNA. It is important that both the DNA and its chromatin are copied accurately to ensure young and healthy cells. Problems with this process are often seen in diseases like cancer. "Even though this process keeps us healthy, we still don't fully understand how DNA and chromatin are simultaneously copied", says Francesca Mattiroli, group leader.
A unique slowdown alarm
"We found that the copying of chromatin has a direct effect on the mechanisms that copy DNA itself", explains Mattiroli. She and her team found that this effect happens through an unusual stress response. "If there is a problem with DNA packaging, the cell quickly senses this issue. But instead of triggering a typical stress response, the cell responds by slowing down its cycle of growth and division, without stopping it completely", she says. The slower cycle still allows the cell to divide, but the new cells often struggle to continue to grow, preventing them from dividing again.
"So, these mechanisms, which copy DNA and its packaging, are closely connected to cell growth", Mattiroli says. This discovery paves the way for new studies on these pathways and how DNA packaging can control cell growth. In the future, this knowledge could help to find new treatments for diseases like cancer.
A true team effort
"This project was a real adventure for our biochemical lab," says Mattiroli. "Without the collaboration with Alexander van Oudenaarden's lab and our other collaborators, this work would have not been possible. The technology created by Jeroen van den Berg and Vincent van Batenburg was perfect to address the questions we wanted to answer." The research was truly a team effort, with key contributions from co-first authors Jan Dreyer, Giulia Ricci, Jeroen van den Berg as well as from Vivek Bhardwaj and Janina Funk. "I really enjoyed learning all of these new things, thanks to the highly collaborative spirit of the Hubrecht Institute. I look forward to doing more cell-based research in the future", adds Mattiroli.
Publication
Acute multi-level response to defective de novo chromatin assembly in S-phase. Jan Dreyer*, Giulia Ricci*, Jeroen van den Berg*, Vivek Bhardwaj, Janina Funk, Claire Armstrong, Vincent van Batenburg, Chance Sine, Michael A. VanInsberghe, Rinskje B. Tjeerdsma, Richard Marsman, Imke K. Mandemaker, Simone di Sanzo, Juliette Costantini, Stefano G. Manzo, Alva Biran, Claire Burny, Marcel A.T.M. van Vugt, Moritz Völker-Albert, Anja Groth, Sabrina L. Spencer, Alexander van Oudenaarden, Francesca Mattiroli#. Molecular Cell, 2024.
*equal contribution
#Corresponding author
About Francesca Mattiroli
Francesca Mattiroli is a group leader at the Hubrecht Institute since January 2018. Her group investigates chromatin dynamics during DNA replication and repair. The Mattiroli group uses biochemical reconstitutions, structural approaches and cell biology to elucidate the biophysical and structural properties of chromatin and its key regulatory factors, such as histone chaperones. Chromatin organisation controls cell fate and survival, and it is often deregulated in diseases such as cancer. By determining the molecular basis for chromatin control of cell identity, we contribute to the development of potential new strategies for cancer treatments.
About the Hubrecht Institute
Research at the Hubrecht Institute is pioneering in developmental and stem cell biology. The institute encompasses 20 research groups that perform fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms.The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences ( KNAW ), situated on the Utrecht Science Park. Since 2008, the Hubrecht is affiliated with the UMC Utrecht. This allowed the institute to grow into an internationally renowned research institute and facilitated the link with (pre)clinical research. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory ( EMBL ) based on shared institutional goals, scientific synergy and complementarity.
