Centromeric Recombination: friend or foe?

Accurate cell division is imperative for organism development, At the heart of this critical process lie the centromeres, pivotal in orchestrating kinetochore assembly and ensuring the accurate segregation of chromosomes during cell division. In most eukaryotic organisms, centromeres are comprised of repetitive DNA sequences, a composition that often gives rise to intricate DNA structures, hindering the smooth progression of DNA replication and rendering centromeres vulnerable to fragility. Due to its repetitive nature, centromeric DNA is prone to recombination, previously considered detrimental. Our recent research challenges this notion, showing that Homologous Recombination (HR) safeguards centromeres against illegitimate recombination and other mutagenic pathways. In agreement, the complete sequencing of the human genome suggested that centromeric recombination at an evolution time scale dictates centromeric specification. This proposal aims to uncover the ingenious strategies employed by centromeres in utilising recombination to enhance diversity while maintaining genomic stability. We will identify the pivotal elements involved, comprehend their roles in centromeric function, and explore the impact of their misregulation on disease development. We will provide the first systematic account of recombination mechanisms at centromeres and will answer longstanding questions about repeat variability, its correlation with diversity and mutagenesis, and its impact on cell identity and tumorigenesis.