Oxidative DNA damage drives centromere fragility and chromosome instability.

Oxidative DNA damage at centromeres promotes chromosome instability, with lesions leading to DNA breaks and aneuploidy in pre-tumorigenic cells.

• Why it matters: Centromere fragility contributes to chromosome rearrangements in cancer, but the mechanisms behind this instability are not fully understood, limiting potential interventions.
• What they did: Using a chemoptogenetic system to generate singlet oxygen specifically at centromeres, the study uncovers how oxidative base lesions impair DNA synthesis, destabilize chromatin, and cause DNA breaks that persist across cell cycles.
• The result: Findings demonstrate that centromeric oxidative damage acts as a cell-cycle-sensitive DNA damage sensor, driving mitotic defects, chromosome translocations, and instability, which may facilitate tumorigenesis.