It’s a wrap: how cells package newly-made DNA – PhD Defense Giulia Ricci

Our bodies continuously generate new cells for growth and tissue repair through the process of cell division. DNA is tightly packaged within chromosomes to fit in the cell nucleus. To achieve this, DNA is wrapped around histone proteins to form structural units known as nucleosomes. A multitude of these nucleosomes make up chromatin. Before a cell divides, its DNA must be copied and its chromatin structure re-established. This ensures that the two daughter cells receive identical DNA after division and that the heritable patterns of gene regulation are preserved. The latter is often referred to as the epigenome.

New nucleosomes

To enable DNA replication, the chromatin structure is temporarily disrupted. The two original DNA strands are separated so that a complementary strand can be generated for both. When this is complete, the newly generated DNA is immediately wrapped around histones, forming new nucleosomes for both daughter cells and restoring the chromatin structure. Key molecules in this process are histone chaperones. Giulia centered her research around Chromatin Assembly Factor-1 (CAF-1), one specific histone chaperone that is responsible for linking the histones to newly made DNA, so that chromatin can be rapidly re-established.

“If nucleosome assembly is not tightly coupled to replication, genome stability and transcription processes may be negatively affected,” Giulia explains. She investigated how CAF-1 coordinates nucleosome assembly during DNA replication, and what happens when this coordination fails.

Symmetrical strand service

Giulia explored whether CAF-1-mediated nucleosome assembly is equally coupled to both newly generated DNA strands. She found that this process is symmetrical: the histone chaperone places histones equally on both strands, indicating that new chromatin assembly does not introduce strand-specific differences.

The histone chaperone: a critical safeguard of epigenome integrity

Giulia studied what happens during nucleosome assembly when CAF-1 fails. She discovered that when this histone chaperone is absent, problems occur very early: already before the cell activates its usual emergency response systems, DNA copying slows down, chromatin restoration is disrupted and gene expression changes. The protein p53, which acts as cellular watchdog, notices these problems and stops cell division. These findings highlight the important role of CAF-1in safeguarding epigenome integrity and cell replication. Furthermore, Giulia discovered that some functional interactions of CAF-1 are indispensable for sustaining DNA replication, while others are not: the different roles of CAF-1 are mechanistically separable.

Fundamental science as fuel

Giulia’s work focused on uncovering fundamental cellular mechanisms, not directly related to a specific disease. She saw this as part of the beauty of basic research: to pursue understanding for its own sake, without knowing its future impact. “I strongly believe that fundamental science forms the foundation that fuels all other research,” Giulia tells.

An introspective journey

Giulia is happy with how her PhD journey has unfolded and is thankful for the continuous support of her supervisor Francesca and her lab mates. One of the highlights of her PhD was the possibility to publish and present her own work: “Presenting our work to the scientific community was a great responsibility, but also incredibly exciting,” she recalls.

Giulia emphasizes how a PhD journey inevitably includes personal alongside academic challenges. “Science requires dedication and motivation, but also learning to function in the midst of multiple responsibilities, trusting yourself and not fearing failure.” Sometimes, Giulia found it difficult to not define herself by her work. “When you’re deeply invested, setbacks feel personal and letting go is hard. It takes conscious effort and perspective to navigate it well,” she summarizes.

To students considering a PhD, Giulia advises: “If you’re curious and enjoy challenges, a PhD might be for you.” She adds that choosing the right lab is crucial: “Working at the Hubrecht Institute with my supervisor and team made all the difference.”