Student Theses and Dissertations

Date of Award

2010

Document Type

Thesis

RU Laboratory

Funabiki Laboratory

Keywords

chromosome segregation, chromosomal passenger complex, Aurora B, spindle assembly, xenopus egg

Abstract

Life depends on faithful DNA segregation. The molecular underpinnings controlling this segregation are not fully understood. Here I describe the role of the chromosomal passenger complex (CPC) in the regulation of chromosome segregation, using Xenopus egg extracts. The CPC contains the kinase Aurora B, which is well known for its phosphorylation of serine 10 on histone H3 (H3S10). While this phosphorylation is a hallmark of M-phase, its functional significance is enigmatic. In the first part of my thesis, I, with my collaborators, provide a molecular function for this phosphorylation in the chromosomal dissociation of HP1 (heterochromatin protein 1) in M-phase. The phosphorylation of H3S10 by Aurora B ejects HP1 from its stably methylated histone H3 lysine 9 (H3K9) chromatin binding site, clearly demonstrating the existence of a “methyl/phos switch.” While the significance of this chromosomal HP1 removal is unclear, I propose that it functions in proper M-phase chromosome compaction. In eukaryotes, chromosome segregation depends on spindle formation. Chromosome-induced spindle assembly requires the chromosomal recruitment and activation of Aurora B. How this chromosome-activated kinase spatially disseminates signals that lead to spindle formation remains unclear. In the second part of my thesis, I show that CPC must detect chromosomes and microtubules to support spindle assembly. While the CPC is enriched on chromosomes in metaphase, I establish that a fraction of the CPC is targeted to the metaphase spindle. I demonstrate that this understudied metaphase CPCmicrotubule interaction is required to target chromosomally activated Aurora B to emerging microtubules near chromosomes for spindle assembly. I propose that the dual detection of chromosomes and microtubules by the CPC ensures that spindle formation is spatially limited to the vicinity of chromosomes. The spindle assembly checkpoint is vital for faithful chromosome segregation, as the checkpoint monitors the proper attachment of chromosomes to the spindle. In the third part of my thesis, based on preliminary data, I discuss the possibility that the dual detection of chromosome and microtubules may also function in the signaling of this checkpoint. Together, my work demonstrates three different functions of the CPC that impinge on chromosome segregation and genomic integrity.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/374

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