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Aneuploidy and chromosomal instability.

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Call No.	Ph.D. 2010
Author	Thompson, Sarah L.
Title	Aneuploidy and chromosomal instability.
Date	2010
Abstract	Most solid tumors are aneuploid, and many tumor cells persistently mis-segregate whole chromosomes at an elevated rate in a process called chromosomal instability (CIN). CIN occurs due to loss of chromosome segregation fidelity during mitosis, however, the cause of these chromosome segregation errors in tumors remains unknown. Here I show that the most common mitotic defect in multiple cancer cell lines with CIN are lagging chromosomes in anaphase caused by a specific type of malattachment of microtubules to kinetochores called merotely. Overexpression of microtubule depolymerizers Kif2b and MCAK in cell lines with CIN reduces levels of merotely and chromosome lagging and restores faithful chromosome segregation. In addition, diploid cells can be induced to mis-segregate chromosomes at levels similar to cells with CIN by persistently elevating the levels of merotely, however, aneuploid cells produced from these diploid cells do not propagate efficiently and the population remains diploid due to growth arrest in the aneuploid cells caused by stabilization of p53 and p21. When p53 or the stress kinase p38 is inhibited in diploid cells that have been induced to mis-segregate chromosomes, aneuploid cells can propagate and are maintained in the population. In the diploid HCT116 colon cancer cell line, deletion of p53 combined with several generations of induced persistent chromosome missegregation is sufficient to produce aneuploid, CIN clones. Subclones derived from these clones remain chromosomally unstable despite no longer being induced to missegregate chromosomes, which suggests aneuploidy itself causes self-perpetuating CIN. Finally, when merotely is elevated through drug washouts or depletion of MCAK, Kif2b, CENP-E, or Kif18a, there is a high incidence of both lagging chromosomes and mis-segregation, but most chromosomes mis-segregate without evidence of lagging. Most lagging chromosomes segregate to the correct daughter cell, where they form micronuclei which can be reincorporated into the main nucleus during the next round of mitosis. Thus lagging chromosomes are an indicator of high levels of merotely and missegregation, but not necessarily the cause. Together, the data in this thesis suggest elevated levels of mis-segregation must combine with mutations that allow for tolerance of nondiploidy to generate the levels of aneuploidy seen in tumors.
Description	xiv, 281 leaves : ill. (some col.) ; 28 cm.
Format	application/pdf
Advisor	Compton, Duane A., Cole, Michael D., Whitfield, Michael L., Sluder, Greenfield
Subject	Aneuploidy. Chromosome abnormalities. Tumors -- Genetic aspects. Microtubules. Medical Term: Chromosomal Instability.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.361

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	ANEUPLOIDY AND CHROMOSOMAL INSTABILITY A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Sarah L. Thompson DARTMOUTH COLLEGE Hanover, New Hampshire 25th May 2010 Examining Committee: ________________________ Duane A. Compton (chair) ________________________ Michael Cole ________________________ Michael Whitfield ________________________ Greenfield Sluder ________________________ Brian W. Pogue, Ph.D. Dean of Graduate Studies

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Aneuploidy and chromosomal instability.

Aneuploidy and chromosomal instability.