Every time a human cell divides, its chromosomes lose a tiny bit of their protective caps—telomeres—because the cells lack enough of the enzyme telomerase to fully rebuild them. This gradual shortening eventually makes telomeres look like broken DNA, triggering damage responses that can lead to genome instability, cancer, and the tissue decline seen in ageing. The researchers are using budding yeast—a simple organism whose telomere biology closely mirrors our own—to answer two fundamental questions: how cells cope when telomerase is scarce, and how the DNA damage response alters telomerase activity at both broken ends and healthy telomeres. They have already discovered that yeast can boost telomerase by changing their chromosome sets, and that DNA damage signals can paradoxically stimulate telomerase at telomeres while suppressing it at breaks. This is fundamental science with no immediate practical application. However, because the core proteins and pathways are conserved from yeast to humans, a molecular-level understanding of these regulatory mechanisms could eventually inform strategies for treating genetic disorders like dyskeratosis congenita, managing age-related tissue failure, and designing cancer therapies that exploit telomere-driven genome instability.
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Telomeres are the natural ends of linear chromosomes present in many organisms, from unicellular fungi and algae to humans. Telomeres do not encode any genes but are important for accurate chromosome maintenance by protecting chromosomes against degradation and fusion to other chromosomes. They consist of short DNA repeats (TTAGGG in humans) which allow cells to differentiate them from broken DNA ends. Cell replicate their chromosomes every time before they divide and telomeres require a special enzyme, telomerase, for their replication. If there is no or very little telomerase telomeres shorten with each cell division and once they have become critically short they resemble broken DNA ends and can no longer protect chromosomes. Consequently, chromosomes undergo DNA loss, fusions to other chromosomes and further genome-destabilizing events, which may abolish cells' ability to function and lead to cancer in humans. Most human cells express very little telomerase and due to the resultant telomerase insufficiency telomeres in our cells become shorter with age. This telomere shortening has been linked to impaired tissue homeostasis, wound healing and immune response in elderly. Furthermore, mutations in human telomerase genes result in accelerated telomere shortening, bone marrow failure, nail dystrophy, abnormal skin pigmentation and increased risk of cancer. Therefore, studying how telomerase is regulated and how cells deal with critically short telomeres is important for our understanding of certain human genetic disorders, cancer development and human ageing. This research proposal is focused on two major questions: 1.How do cells deal with telomerase insufficiency? Telomerase insufficiency is not wide-spread in nature but importantly it is one of the key signatures of ageing human cells as well as pre-cancer cells on their way to malignancy. For the first time, we have reported a system for studying telomerase insufficiency in a simple model system of budding yeast and used it to show that cells with telomerase insufficiency can boost telomerase by altering their chromosome set (karyotype) so that it slows the rate of cell growth. We aim to investigate how the rate of cell growth affects telomerase and its ability to extend telomeres, and to identify and characterise other mechanisms of overcoming telomerase insufficiency. We will also study if short telomeres might trigger karyotype changes as we have preliminary evidence that recombination, which is known to be increased at short telomeres, is involved in altering karyotype. 2.How are telomeres and telomerase regulated during DNA damage response? Critically short telomeres, often arising as a result of telomerase insufficiency, resemble DNA breaks and induce DNA damage response - a set of cell reactions directed at activation of DNA repair and pausing cell division until the repair is complete. In our prior experiments we discovered a pathway that regulates yeast telomerase in response to DNA damage. Intriguingly, the regulation had opposite effects on telomerase at broken chromosome ends and at telomeres: telomerase was inhibited at DNA breaks (to prevent erroneous break repair by telomerase) but stimulated at telomeres as a result of break repair by a specific mechanism called break induced replication. We are proposing to dissect this regulation at the molecular level to elucidate the interplay between telomerase, DNA repair and DNA damage response in order to understand regulatory pathways providing accurate DNA repair and telomere maintenance in cells with telomerase insufficiency and/or DNA damage. Because all the key proteins and pathways under study are highly conserved from yeast to humans our findings will be relevant to human cells. This research has important implications for approaching human health problems associated with genome instability, such as normal human ageing, multiple genetic disorders, and especially for understanding cancer cause and therapy.
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