Silenced but not Silent: how heterochromatin promotes its maintenance and stability

Our DNA carries the blueprint of life, but it is not left unprotected. Instead, it is packaged into chromatin, which can be organized in a loose form (euchromatin) or a compact form (heterochromatin). This packaging not only regulates which genes are active, but also plays a key role in protecting and repairing our DNA. Heterochromatin, however, poses a special challenge: its repetitive nature makes it more difficult to repair DNA damage, increasing the risk of errors that can lead to cancer and other diseases. In my thesis, I investigated how heterochromatin is organized and regulated in different contexts: healthy human cells, cancer, and the evolution of organisms. I developed a new system to induce precise DNA breaks, allowing us to compare repair processes in eu- and heterochromatin. We found that breaks in heterochromatin often move away from this domain in order to be repaired. I also studied how cancer-related changes in heterochromatin proteins impact genome stability. Our results showed that misregulation of these proteins correlates with genomic instability in tumors, highlighting their importance in cancer development. Finally, I explored the evolution of heterochromatin repair mechanisms in different fruit fly species, uncovering rapid changes in sequence in key repair proteins that shape how heterochromatin damage is handled, while function remained consistent. Together, these findings reveal that heterochromatin is a dynamic yet fragile environment. Its proper regulation is essential to safeguard genome stability and may hold the key to preventing diseases such as cancer.