Research

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 (G_1-3T in budding yeast and 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. Mutations in human telomerase genes result in accelerated telomere shortening, bone marrow failure, nail dystrophy, abnormal skin pigmentation and increased risk of cancer.

Budding yeast Saccharomyces cerevisiae is a simple and robust model system proven efficient for studying genome integrity in eukaryotes. DNA damage repair and checkpoint activation machineries are conserved from yeast to humans. Likewise, there are a lot of similarities in telomere maintenance between the two organisms. Therefore, we use yeast to investigate genome maintenance mechanisms common to most eukaryotes, including humans. Our research is focused on addressing 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) to a specific aneuploidy (chromosome VIII) which slows the rate of cell growth through downregulation of ribosome biogenesis. Interestingly, this aneuploids have increased abundance of telomerase RNA and telomerase accessory subunits (Figure 1). We are investigating how the rate of cell growth and changes in stoichiometry of telomerase components affects telomere metabolism, and if there are other mechanisms of overcoming telomerase insufficiency.

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 (Figure 2). 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 (BIR). We are dissecting 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.