The shielding role of the nuclear periphery against the genetic and non-genetic consequences of DNA damage (ChromoSENSOR)

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A key feature of the mammalian nucleus is the non-random arrangement of the genome within the nuclear space, which is linked to how cells cope with DNA damage. Tethering heterochromatin to the nuclear lamina to form the Lamina Associated domains (LADs), protects repetitive DNA from illegitimate recombination and enhances the ability of the nucleus to resist mechanical forces, which can lead to DNA damage. In addition to jeopardizing genomic integrity, DNA damage has non genetic consequences. It affects the integrity of the nuclear lamina, leads to changes in the epigenome and alters the propensity of DNA to associate with the nuclear periphery. All these changes, need to be restored to maintain cell fitness. The mechanisms by which non-random genome organization, and particularly LADs, protect cells against the genetic and non-genetic consequences of DNA damage are unknown.We will use innovative protein-targeting strategies to induce LAD-specific DNA breaks, to unravel how LADs control DNA repair pathway choice to supress recombination between repeats and whether compromising LAD integrity correlates with structural variations in cancer genomes. We will determine whether the epigenome is restored after DNA repair and whether LAD-position is inherently altered, impacting cell identity. Finally, using precise mechanical manipulation of the nucleus, we will investigate how the nuclear periphery protects the genome from mechanical stress-induced DNA damage. This proposal will uncover the mechanisms that preserve LAD genome and epigenome integrity and will have a significant impact on our understanding of how cell fitness after DNA damage is enforced. We will also gain insight into the complex relationship between chromatin mechanics and DNA damage and reveal the changes that the nuclear periphery undergoes to protect genome integrity. This knowledge will be essential to determine how we can engineer chromatin state to exploit it for cancer treatment.