HETREPAIR · Heterochromatin repair: mechanisms and roles across scales

Cells face continuous challenges from insults that damage their DNA. To safeguard DNA integrity, a range of repair mechanisms have evolved, which are crucial for organismal survival. However, the eukaryotic nucleus contains different chromatin domains, each requiring specific repair mechanisms to ensure genome stability. In particular, the compact and transcriptionally silenced heterochromatin domains, which are riddled with repetitive DNA and developmental genes, are a challenging environment to repair DNA damage. Despite covering a substantial amount of our genome and being essential for organismal viability and development, heterochromatin remains poorly understood in its response to DNA damage. Heterochromatin domains possess specific molecular and biophysical properties, which I hypothesize necessitate unique chromatin responses at the damaged site to ensure effective repair and maintain genome stability. The aim of this proposal is to identify the dynamic responses to DNA damage in heterochromatin domains and determine their role in maintaining genome stability and tissue health. I will study this across scales, utilizing our recently developed in vitro reconstitution systems that mimic DNA damage in heterochromatin, as well as our unique in vivo systems to study and manipulate heterochromatin repair in fruit fly tissue. These approaches will be integrated with state-of-the-art proteomics, single-cell chromatin analyses and live imaging to identify the mechanisms of DNA repair in heterochromatin, and ultimately determine their impact on genome maintenance and tissue homeostasis. Unravelling chromatin dynamics during DNA repair in heterochromatin has the potential to yield broader insights into their role in other essential nuclear processes such as DNA -replication and -transcription. Importantly, HETREPAIR could in the long-term shed light on how heterochromatin repair processes are disrupted in disease and how these can be exploited during treatment.