Role of kinetochore proteins in chromosome segregation

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Accurate chromosome segregation is crucial during mitosis because its disruption can result in aneuploidies and genomic rearrangements that promote tumor evolution and metastasis in cancer cells. Chromosome segregation is mediated, in part, via the attachment of spindle microtubules to kinetochores. These large proteinaceous structures assemble on each chromosome at a site called the centromere, which is defined by nucleosomes containing the histone variant CENP-A. My lab uses Xenopus egg extracts, human cell culture, and a variety of experimental approaches to understand the molecular signals at chromosomes, centromeres, and kinetochores that regulate kinetochore assembly and kinetochore-microtubule attachment during mitosis. A long-term focus of the lab has been how the mitotic kinase Aurora B, a key cancer drug target, regulates kinetochore assembly and function. Aurora B, along with INCENP, Survivin, and Borealin, form the Chromosomal Passenger Complex (CPC). The CPC is involved in almost every mitotic and meiotic process in eukaryotes, including kinetochore assembly, ensuring bi-orientation of sister chromatids, activating the spindle checkpoint, promoting cytokinesis, and assembling the spindle in oocytes and embryos. Work from my lab has illuminated CPC functions at centromeres and kinetochores that ensure the equal segregation of chromosomes. These include showing that CPC localization at centromeres is required to detect and respond to errors in attachment, discovering that the CPC plays an Aurora B-independent role in the assembly of the inner kinetochore, demonstrating that INCENP-mediated localization of Aurora B to the inner kinetochore is required for the assembly of the outer kinetochore; and defining the interaction between the CPC and Sgo1. Our research has brought us into new areas as well, and we have focused on the organization of the inner kinetochore and centromeric chromatin. We have leveraged collaborations to determine how the inner kinetochore attaches to centromeric chromatin and to discover that the transcription machinery regulates the loading and function of the structural maintenance of chromosomes (SMC) complex condensin, a significant player in the organization of centromeric chromatin and bi-orientation. Our current research found that the CPC promotes the complete assembly and immobilization of the inner kinetochore during mitosis by regulating a centromere-proximal pool of the SMC complex cohesin. We will determine how cohesin and condensin regulate the mitotic inner kinetochore and investigate other cell cycle-dependent mechanisms required for reorganizing the inner kinetochore at mitotic entry. These studies will unlock new insights into centromere and kinetochore organization and function and open new avenues for chemotherapeutic intervention.