Research
The Karlseder Lab focuses on understanding the functions of mammalian telomeres. Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are crucial in DNA replication, tumor suppression, and aging. Every time a primary human cell divides, its telomeres get shorter, until critically short telomeres lead to terminal cell cycle arrest. We believe that a better understanding of this telomere shortening process will lead to an ability to influence the aging process, and as a result to the restriction of cancer cell growth.
Currently, we work on several aspects of telomere dynamics, namely the involvement of telomeres in premature aging diseases, interactions between the DNA damage machinery and telomeres, and telomere processing during the cell cycle.
Shown on the right is an image of chromosomal DNA from human cells in the metaphase stage of mitosis. Using a technique called Fluorescent In Situ Hybridization (FISH), the telomeric DNA can be labeled with a fluorescent tag (seen in green), while the genomic DNA is labeled with DAPI (blue).
Current projects
Our laboratory discovered that cells from Werner Syndrome patients lose individual telomeres, a phenomenon we termed Sister Telomere Loss (STL). STL telomeres were found to always be the ones replicated by lagging strand synthesis, which led us to propose a model, wherein the WRN helicase is required for efficient replication of the telomeric G strand. We could also demonstrate that STL leads to the accumulation of genomic instability, raising the hypothesis that tumors associated with Werner Syndrome result from a telomere replication dysfunction. Current research investigates the redundancy of WRN with other RecQ helicases.
Our lab's research of telomere dynamics led to the finding that functional telomeres are recognized as double stranded breaks in G2 of the cell cycle. During a brief period after DNA replication telomeres recruit the DNA damage machinery, suggesting that this machinery is required for telomere processing. Further detailed analysis of telomeres during the cycle revealed that telomere processing occurs in two phases. In Phase 1 telomeres are replicated, and an ATR dependent DNA damage response monitors potential fork stalling and triggers repair synthesis and replication restart, when necessary. Then, after complete replication of telomeres, an ATM dependent damage response leads to recruitment of the homologous recombination machinery, which is required for formation of a protective structure at the end of chromosome. These results demonstrate that telomeres are processed similarly to double stranded breaks, and the cellular DNA repair machinery is involved in formation of functional chromosome ends.
We are also exploring telomere dynamics, as well as telomerase function in the nematode C. elegans, with the goal of understanding worm telomeres better, and using this genetically traceable organism for genome-wide screens.
