Chromosomal alterations can arise from numerous events, including errors during cell division or repair of damaged DNA. Of these errors, segregational defects such as anaphase bridges and multipolar spindles play a major role in chromosomal instability, leading to tumorigenesis.
Bridges can theoretically be produced by several mechanisms including telomere-telomere fusion, persistence of chromatid cohesion into anaphase or repair of broken DNA ends. DNA damage can induce anaphase bridges following exposure to agents such as hydrogen peroxide or ionizing radiation (IR). Our hypothesis is that while the majority of double strand breaks (DSBs) are repaired, to restore the original chromosome structure, incorrect fusion events also occur leading to bridging and that bridge formation allows cells to bypass the apoptotic pathways that are activated in response to DNA damage. To test this, we set out to determine what pathways the cells use to heal the damage and form bridges. Our data suggest that neither of the two major pathways used by the cell for repair of double strand breaks, homologous recombination (HR) and non-homologous end joining (NHEJ), is required for bridge formation. In fact, the NHEJ pathway seems to play a role in the prevention of bridges. When NHEJ is compromised, the cell appears to use HR to repair the break, resulting in increased anaphase bridge formation. Moreover, intrinsic NHEJ activity of different cell lines appears to be correlated with induction of bridges from DNA damage. Our preliminary data also suggest that cell lines with high levels of bridging are capable of apoptosis, yet further experiments are required to see if blocking bridging can enhance cell death.
Multipolar spindles are aberrant mitotic figures when a cell divides into two or more poles, which can lead to uneven segregation of the chromosomes. In our studies, we found that IR treatment can lead to an increase in multipolarity shortly after treatment and changes the distribution of spindle pole components. Initial observations on the splitting of centrosomal proteins following IR treatment are presented.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11082006-135315 |
| Date | 26 January 2007 |
| Creators | Acilan, Ceyda |
| Contributors | Dr William Saunders, Dr Graham Hatfull, Dr Deborah Chapman, Dr Jeffrey Hildebrand, Dr Richard Wood |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11082006-135315/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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