The processes that ensure accurate chromosome segregation in mitosis and meiosis are critical for cellular viability and stability. The centromere is an essential chromosomal structure with multiple functional roles necessary for faithful segregation of replicated chromosomes to daughter cells. This project will provide new insights into molecular mechanisms that lead to formation and maintenance of centromeres. In addition, the project will provide research and training opportunities to postdoctoral, graduate, undergraduate and high school students in the San Antonio area, many of whom are under-represented minorities and underprivileged.
The goal of the project is to determine the factors and steps responsible for centromere formation and maintenance. Ubiquitylation of CENP-A protein is essential for CENP-A centromere deposition and assembly; hence, the hypothesis is that identification of ubiquitin-dependent CENP-A interactors will provide crucial information about mechanisms that control centromere assembly and maintenance. The following specific aims test this hypothesis: (1) determine the role of RAD50 (and the MRN complex) in CENP-A deposition at the centromere and its stability in centromeric nucleosomes (preliminary data implicate these proteins in ubiquitylation-dependent interactions with CENP-A); and (2) determine the role of R-loops in CENP-A deposition at the centromere (preliminary data implicate RNA helicase A, which is involved in R-loop formation and resolution, in ubiquitylation-dependent interactions with CENP-A). The intellectual significance of this work lies in novel mechanistic information that is vital to understanding the fidelity of chromosome segregation.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
