Summary Cancer cells harbor signs of genomic instability, including genome rearrangements, which can contribute to tumor development. Faithful DNA repair combats this instability and is a powerful tumor suppressor mechanism whereas erroneous repair leads to pathological outcomes. The inherent genomic instability of cancer cells makes them more vulnerable to a high damage burden and DNA damaging therapies are amongst the most widely used and most successful cancer therapies. DNA repair is enabled within nuclear compartments or repair domains. Spatial organization of repair facilitates biochemical reactions, restricts reactions to specialized compartments while bringing DNA lesions in close proximity, thus favoring rare aberrant genome rearrangements. We have made initial progress in revealing the mechanisms underlying the 3D re-organization of the genome following DNA damage. Based on our seminal discovery of mechanical forces driving the 3D arrangement of the genome following damage, we propose to better understand the mechanisms responsible for the assembly of DNA repair domains and to evaluate the physio-pathological consequences of assembling these domains following treatment with chemotherapeutic drugs. We will also explore the connection between DNA replication and DNA repair in 3D. Our studies should reveal common rules governing the organization of DNA transactions in 3D, which in turn have the potential to identify novel vulnerabilities for the most common modalities of cancer treatment.

Narrative The proposed research is highly relevant to public health. The spatial organization of DNA repair establishes the balance between normal repair, a tumor suppressor mechanism, and pathological repair, yielding oncogenic chromosome rearrangements. Elucidating how DNA repair is organized 3D following DNA damage will help understand the modality of action of cancer therapies.