fishikaw -at- lif.kyoto-u.ac.jp
miyoshi.tomoichiro.5e -at- kyoto-u.ac.jp
nakaoka.hidenori.6n -at- kyoto-u.ac.jp
Stable maintenance of genetic information is essential for cell viability. Genetic instability, a condition in which the genome is not properly maintained, causes numerous pathologies including cancer and aging. Telomeres, the ends of chromosomes, play a pivotal role in this process. We are interested in how telomeres protect genetic information from intrinsic and extrinsic insults. Aging can be defined as the accumulation of damaged cells caused by various stresses. Stress is generally considered to be non-adaptive. However, low-dose stress can act in an adaptive role by fostering cell resistance to prospective lethal stresses. This process is termed acquired tolerance (or hormesis) and its molecular mechanisms remain largely unknown. We are trying to understand how acquired tolerance is induced molecularly. Arguably, cancer cells in vivo acquire stress resistance through experiencing ever-lasting environmental changes. As such, inhibiting the acquired tolerance in cancer cells may lead to fragility of cancers to various stresses, including iatrogenic ones.
- Molecular understanding of how telomeres protect DNA ends in fission yeast and mammals.
- Functional roles of acquired tolerance in various physiological and pathological conditions.
- Mechanism of retrotransposition and its impact on genomic instability in the mammalian genome.
- Development of therapeutic strategies for cancer by elucidating the mechanisms of cellular senescence.
- Mechanism of genomic instability induced by chromosome end-to-end fusions.
Ingeneral, cells exposed to lethal stress undergo cell death (A). However, cells preconditioned with mild stress can become resistant to subsequent lethal stresses (B). This process is called acquired tolerance or hormesis: an adaptive behavior that is crucial for survival in an ever-changing environment. In vivo, cancer cells can experience environmental changes such as hypoxia and iatrogenic stress. This is in contrast to normal cells that live in a stable niche given by the tissue. It is possible that cancer cells are pre-conditioned by the environmental changes to prepare for the prospective lethal stress. Therefore, inhibition of this acquired tolerance may make cancer cells sensitive to anti-cancer therapeutics.