Protein interactions at the human topoisomerase II[alpha] promoter : a thesis presented to Massey University in partial fulfilment of the requirement for the degree Doctor of Philosophy in Biochemistry
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Date
2009
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Massey University
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Abstract
Among women in the 45 to 64 age group, over half of the recorded deaths are from cancer,
breast cancer being the most common. Just over 30% off all deaths in New Zealand women
is caused by breast cancer. Treatment of cancer is difficult, not only due to the physiological
and immunological similarities between a cancer cell and a normal cell, but also due to the
high cardiotoxicity of many treatments, and also the problems related with the development
of resistance. Approximately 40% of the cancer cells treated with the chemotherapy drug
doxorubicin will become resistant to treatment. Drug efficacy is strongly associated with the
proliferation status of a cell, as cancer cells divide rapidly, this can often be the defining
factor between effective treatments or the development of resistance. Central to this
proliferation status is an enzyme known as topoisomerase IIa. This essential enzyme is
expressed in all cells and is required to relieve the torsional stress in DNA that is created
during normal cellular processes. A number of commonly used anti-cancer drugs have been
found to target topoisomerase IIa in cancer cells and significantly, during the development of
drug resistance levels of topoisomerase IIa enzyme have been found to be reduced in some
cell lines and tumours. There are a number of factors that can modulate the amount of
topoisomerase IIa enzyme found in a cell, and one of the ways to understand this is to
examine the regulation of the topoisomerase IIa gene, most importantly the proteins that
interact with the promoter region to direct transcription.
The human topoisomerase IIa promoter has been found to be regulated by a number of
transcription factors that can bind to their cognate sequences. The introduction of mutations
within specific sequences of the topoisomerase IIa promoter has enabled the identification of
a key regulatory region within the promoter, a sequence of DNA that encompasses both the
ICB1 and GC1 regulatory elements. Transcription factor NF-Y is found to bind to ICB1
element, whereas transcription factors Sp1 and Sp3 have been found to associate with the GC
element. However this region of the promoter was also found to bind a fourth
uncharacterised component. This research aims to further define the protein components that
are found to bind to this important ICB1/GC1 regulatory region and distinguish the protein-protein
and protein-DNA interactions that are important for the regulation of the human
topoisomerase IIa promoter.
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Keywords
Human topoisomerase IIα promoter, Human topoisomerase IIalpha promotoer