Ectopic Kinetochore Formation and Endogenous Centromere Dysfunction due to the Over- Expression of CENP-A
Chromosome instability (CIN), a form of genomic instability, is a hallmark of many human cancers. However, the exact mechanisms contributing to CIN in cancers are not completely understood. The centromere, a unique chromosomal domain required for kinetochore formation and faithful chromosome segregation, is a plausible source of CIN as its misregulation has been implicated to cause neo-centromere formation, dicentric behavior, and chromosome bridges, resulting in aneuploidy, genome rearrangements, and micronuclei. The centromere is epigenetically established across cell generations by CENP-A, a histone H3 variant. As the molecular foundation of centromere chromatin, CENP-A is required for all downstream centromere factors and kinetochore structures to localize to the centromere including the constitutive centromere-associated network (CCAN) and KMN (KNL1 complex, Mis12 complex, and Ndc80 complex) network.
In Drosophila, CENP-A overexpression causes milocalization, ectopic kinetochores, and thus, chromosomal missegregation. Uniquely, the overexpression of CENP-A in human cells leads to mitotic defects without neo-centromere formation. With my project, I plan to investigate how the overexpression of CENP-A affects the centromeric identity and to localization of key kinetochore proteins in human cells by elucidating its effects on the CCAN and KMN. As a beginning point for my honors thesis, I am enthusiastic that this study will provide some insight as to how CENP-A OE contributes to CIN.
Message to Sponsor
- Major: MCB (Neurobiology) & Spanish Double Major & BioEngineering Minor
- Sponsor: Rose Hills Independent
- Mentor: Gary Karpen