The centromere is a specialized chromosomal region that is the foundation of the proteinacious kinetochore complex. The kinetochore mediates spindle attachments and ensures high-fidelity segregation of chromosomes during cell division. Regulation of centromere formation during cell division is critical for ensuring high-fidelity transmission of genetic information and is therefore essential for life. Derangements in centromere biology are associated with a wide range of human diseases ranging from sterility to cancer. Specific centromere aberrations observed in aggressive cancers include increased levels of kinetochore protein components, aberrant expression of transcripts from the centromere and expansions of centromeric DNA. Knockdown of kinetochore proteins and centromeric transcripts have been identified as potential cancer targets. However, the process by which centromere dysfunction drives tumorigenesis is unknown. Intriguingly, centromere derangements have also been associated with errors during meiosis. In meiosis, centromere expansion from chromosomal fusions lead to biased transmission of the chromosomal fusions to children in affected women and lead to sterility in affected men. Yet the mechanism by which variation in centromere size leads to meiotic dysfunction remains poorly understood.
Three specific aims are proposed to identify the effect of centromere expansions on mitosis and meiosis. A major hurdle in the study of centromere biology is the dearth of tools to specifically create and expand centromeres within a genome.
Specific Aim 1 will address this need through the generation of a novel tool for generating inducible, targeted centromeres.
In specific aim 2, the role of targeted centromere expansions in a developing D. melanogaster wing will be studied. This will be the first study of the effect of centromere expansion on a euploid developing tissue. Finally, in specific aim 3, the effect of centromere expansion on oogenesis and spermatogenesis will be determined. The results of aim 3 will shed light on the mechanism by which variation in centromere size can lead to meiotic dysfunction. Collectively, these experiments will significantly contribute to the cancer biology, genome structure and evolution fields while also establishing a new approach for generating targetable ectopic centromeres.
The goal of this project is to understand how centromere expansion affects cell division. Derangements of centromere regulation are now widely implicated in a range of aggressive cancers and have been associated with male sterility. Elucidating the mechanisms by which centromere expansions affect cell division has far- reaching clinical implications for cancer and infertility.
