Ectopic Kinetochore Formation and Endogenous Centromere Dysfunction due to the Over- Expression of CENP-A

Summer 2016

Andrew Song : MCB (Neurobiology) & Spanish Double Major & BioEngineering Minor

Mentor: Gary Karpen

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.

To the Rose Hills Foundation, I wish to sincerely express my gratitude for this opportunity to conduct my own individual research project here in Berkeley. This fellowship has allowed me to apply all that I've learned here at UC Berkeley and turn my education into real results. Not only this, but this fellowship will also serve as a springboard as I pursue my future in graduate school. Thank you, Rose Hills Foundation for making all of this possible.