Revealing the Mechanism of HSP104 Transcription Initiation in the ...

INTRODUCTION
The cellular stress response
Cells are continuously exposed to suboptimal growth conditions, generally
termed cellular stresses. They have developed therefore various strategies in order to
survive and even further proliferate and function under these stresses. At the
molecular level these strategies include the activation of several biochemical
machineries. First, the machinery that imposes growth arrest (3, 54, 76, 101, 106,
111, 130) in order to prevent DNA synthesis and proliferation under stress and
damaging conditions. Second, the induction (primarily at the transcriptional level) of
a small number of genes whose protein products are involved in combating the stress
and in repairing the damage inflicted (16, 20, 44, 51, 69). Cell cycle arrest could be
relieved when repair activity is completed and protective systems are active. Third,
the activation of cell death systems, that occurs if the damage is not repairable (5, 11).
This thesis focuses on the mechanisms responsible for the induction of gene
expression in response to stress. The genes expressed in response to stress could be
categorized into two different groups. One group includes genes whose expression is
required to combat the specific stress inflicted (the “specific stress response”). The
other group includes genes that encode repair and protective proteins, but their
activity is not directly relevant to the stress inflicted. They probably serve as a “just
in case” protective measure (the “general stress response”). For example, upon heat
shock, there is specific expression of heat shock protein genes (HSPs) (14, 16, 51, 81,
85), most of which are chaperones that prevent protein aggregation and maintain
proteins in their soluble and active form. However, in parallel to the induction of
HSPs, the cell also induces expression of genes whose products are responsible for
dealing with oxidative stress and/or DNA damage (20, 44, 51, 85). Similarly, when
cells are exposed to DNA damaging agents, some HSPs are induced in parallel to the
induction of DNA repair systems. The induction of many stress-related genes,
including many that are not relevant to the specific stress inflicted, renders the cell
resistant to other stresses or to more severe stresses, a phenomenon known as crossprotection
and thermotolerance (81, 107, 108).
Although revealed to a certain level in prokaryotes, many aspects of the
molecular basis of the cellular stress response in eukaryotes are still enigmatic. It is
not understood, for example, how cells sense stresses such as heat shock (what
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