Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Chromosome segregational defects: their origin, fate and contribution to genomic instability

Luo, Li Z. (2005) Chromosome segregational defects: their origin, fate and contribution to genomic instability. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img]
Preview
PDF (Chromosome Segregational Defects: Their Origin, Fate and Contribution to Genomic Instability)
Primary Text

Download (7MB) | Preview
[img] Video (AVI) (Limovie1)
Supplemental Material

Download (1MB)
[img] Video (QuickTime) (Limovie2)
Supplemental Material

Download (535kB)
[img] Video (QuickTime) (Limovie3)
Supplemental Material

Download (6MB)
[img] Video (QuickTime) (Limovie4)
Supplemental Material

Download (7MB)
[img] Video (QuickTime) (Limovie5)
Supplemental Material

Download (20MB)
[img] Video (QuickTime) (Limovie6)
Supplemental Material

Download (3MB)
[img] Video (QuickTime) (Limovie7)
Supplemental Material

Download (11MB)
[img] Video (QuickTime) (Limovie8)
Supplemental Material

Download (2MB)
[img] Video (QuickTime) (Limovie9)
Supplemental Material

Download (905kB)

Abstract

Chromosome instability (CIN), a continuous change in the structure or number of chromosomes, is proposed to be a key mechanism driving the genomic changes associated with tumorigenesis. One major cause of CIN in cells is chromosome segregational defects occurring during mitosis. Two such examples are anaphase bridges and multipolar spindles, which are common in most cancer cells and many tumor tissues.Anaphase bridges are chromatin bridges in between separating chromosome masses during anaphase, which may result in gene amplification or loss when breaking. We have found that cigarette smoke condensate (CSC) induced anaphase bridges in cultured primary human cells, which in a short time led to genomic imbalances. The frequency of the induced bridges within the entire population decreased with time, independent of the p53-mediated apoptotic pathway. We also showed that CSC induced DNA double-stranded breaks (DSBs) in cultured cells as well as purified DNA. The reactive oxygen species (ROS) scavenger, 2' deoxyguanosine 5'-monophosphate (dGMP) prevented CSC-induced DSBs, anaphase bridge formation and genomic imbalances. Therefore, we propose that CSC induces bridges and genomic imbalances via DNA DSBs. Further analysis in live oral cancer cells shows that cells with anaphase bridges mostly survive and these bridges frequently result in micronuclei formation, indicating that anaphase bridges actively contribute to CIN. Multipolar spindles (MPS) are aberrant mitotic structures when cells divide with greater than two spindle poles, which may result in uneven chromosome segregation. Multipolarity is strongly linked to centrosomal amplification, the mechanism of which remains controversial. We have examined the origin and fate of cells with MPS in real time. In both human embryonic kidney and oral cancer cells, the vast majority of multipolar cells originated from multinucleated cells. The frequency of cytokinesis failure was similar to the frequency of MPS, and each observed bipolar division that ended in a cytokinesis failure led to MPS formation in the subsequent mitosis. While grossly abnormal, these cells are still capable of dividing, often giving rise to a mixed progeny of multinucleated and mononucleated cells. These observations support the model that failure of cytokinesis may be the most common mechanism by which cells form MPS.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Luo, Li Z.liluo@pitt.edu, luoli@ustc.eduLILUO
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSaunders, William Swsaund@pitt.eduWSAUND
Committee MemberWalsh, Charles Jcwalsh@pitt.eduCWALSH
Committee MemberHatfull, Graham Fbiochr@imap.pitt.eduBIOCHR
Committee MemberWood, Richard Drdwood@pitt.eduRDWOOD
Committee MemberGilbert, Susan Pspg1@pitt.eduSPG1
Date: 4 February 2005
Date Type: Completion
Defense Date: 3 December 2004
Approval Date: 4 February 2005
Submission Date: 10 December 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: anaphase bridges; chromosome segregation; genomic instability; multipolar spindles
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12102004-100824/, etd-12102004-100824
Date Deposited: 10 Nov 2011 20:10
Last Modified: 15 Nov 2016 13:54
URI: http://d-scholarship.pitt.edu/id/eprint/10271

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item