DNA is inherently unstable, yet genomes are remarkably stable. Sophisticated DNA damage surveillance and repair pathways have evolved to safeguard genetic material. The failure of these mechanisms leads to various diseases, such as accelerated aging and cancer. Maintaining genome stability is made more challenging by the presence of two distinct genomes – nuclear and mitochondrial – housed in different organelles and exposed to different stresses and mutation rates. The Sfeir lab investigates by how eukaryotic cells coordinate various repair pathways and quality control mechanisms to preserve the stability of both genomes and facilitate their interplay. We focus on two independent yet fundamental questions. First, why have cells evolved a highly mutagenic microhomology-mediated end-joining (MMEJ) process to repair nuclear DNA breaks? Second, how does the nucleus manage perturbations to a circular genome housed in a separate organelle? To address these questions, we employ a multifaceted approach that combines genetic screens and computational predictions with innovative molecular toolkits.