Each day, the DNA of healthy cells suffers from endogenous replicative stress caused by competition between replication forks, transcription sites, and other DNA-binding proteins. This results in 5-50 DNA double strand breaks (DSBs) occurring in each human replicating cell, every 24 hours. Exogenous stressors such as cigarette smoke or alcohol only serve to increase the total amount of DNA damage. DNA DSBs need to be repaired without any loss or gain of genetic code because this could potentially engender a mutation leading to cell death of malfunction. Mutations and cell death caused by DNA misrepair, often exacerbated by deficiencies in repair pathways, underpin many cancers, autoimmune and neurodegenerative diseases. Because of this, a plethora of interacting and redundant repair proteins work within cells to maintain genomic integrity, and much research has been undertaken to try to understand and manipulate these pathways – particularly because inducing genomic stress remains our primary method for treating cancer. However, studying these pathways in vivo has been challenging because of the high signal-to-noise within the dense, homogenous nucleus, and the low level of endogenous DSB induction. Using innovative labeling and super-resolution assays we aim to elucidate damage and repair events at the single molecule scale. In particular we are mapping the high-fidelity homologous recombination repair of collapsed replication forks, and investigating the role of transcriptional silencing within the nucleolus.