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Title: The significance of drug induced DNA damage of telomeres in human tumour cells
Author: Jeyapalan, Jessie Chandika
ISNI:       0000 0001 3590 4729
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2005
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Telomere shortening is a major mechanism to induce telomere uncapping and thus to signal growth arrest and/ or apoptosis and can be caused by different mechanisms, one of which is damage to DNA, to which telomeres appear to be particularly sensitive. Contradictory data exists on the relationship between conventionally used chemotherapeutic drugs and the telomere/ telomerase complex. The aim of the work described in this thesis was to determine whether or not damage to telomeres played a significant role in the cytotoxic action of the anti-cancer drugs cisplatin and etoposide. Two cell lines were used with either short (neuroblastorna cell line SHSY5Y) or long (lymphoblastic T cell line 1301) telomeres. Cytotoxic effects of the drugs were assessed by growth inhibition assays and measurement of apoptosis and cell cycle progression by flow cytometry. Etoposide caused readily detectable DNA strand breakage and led to formation of nuclear foci of phosphorylated histone y-H2A. X. Cisplatin treatment did not induce strand breaks after initial drug exposure but strand breaks and DNA damage foci were detected after further incubation. For cells with either long or short telomeres, no detectable changes in total telomere length or overhang length were observed before apoptosis became manifest. Preferential occurrences of single strand breaks in the G-rich strand of telorneres were not found. Through the development of a dual staining method it was established that drug-induced histone H2A. X foci did not colocalise to the telomeres. Telomerase was transiently activated by lower concentrations of etoposide and its activity decreased only after onset of apoptosis. Taken together, the results show no indication that telorneres and/ or telomeric damage play any preferential role as signal transducers towards apoptosis and/ or growth arrest in either of these cell lines. Also, the protective function of telornerase &-I - seems to be telomere independent. The data are consistent with a model of druginduced growth arrest and apoptosis being triggered by damage elsewhere in the genome.
Supervisor: Not available Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available