Heterochromatin dynamics in the maintenance of genome stability

Cells face continuous challenges from insults that damage their DNA. To safeguard DNA integrity, a range of repair mechanisms has 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. The two main types of heterochromatin are constitutive heterochromatin, associated with pericentromeric repeats, and facultative heterochromatin, required for silencing developmental genes. Repair of double-strand breaks (DSBs) in both constitutive- and facultative- heterochromatin domains requires specific DSB movements and repair responses. Recent results from our lab identify a role for specific histone-modifying activities at DSBs in both facultative- and constitutive-heterochromatin domains. Our data suggest that the transient acquisition of a more open, ‘active’ chromatin state at both facultative- and constitutive- heterochromatic break sites is required for DSB movement, as well as faithful repair in these transcriptionally silenced domains. To further elucidate the molecular mechanisms driving these specific heterochromatic dynamics at break sites, we are employing locus-specific DSB systems in vitro, as well as in Drosophila animals. In addition, we are currently exploring opportunities to study how these heterochromatin dynamics contribute to maintaining genome stability in various tissues of both young and ageing flies.