MedicalResearch.com Interview with:
Professor Jan Karlseder
Molecular and Cell Biology Laboratory
Donald and Darlene Shiley Chair
Salk Institute for Biological Studies
MedicalResearch.com: What is the background for this study?
Response: Telomeres are repetitive stretches of DNA at the ends of each chromosome whose length can be increased by an enzyme called telomerase. Our cellular machinery results in a little bit of the telomere becoming lopped off each time cells replicate their DNA and divide. As telomeres shorten over time, the chromosomes themselves become vulnerable to damage. Eventually the cells die. The exception is stem cells, which use telomerase to rebuild their telomeres, allowing them to retain their ability to divide, and to develop (“differentiate”) into virtually any cell type for the specific tissue or organ, be it skin, heart, liver or muscle—a quality known as pluripotency. These qualities make stem cells promising tools for regenerative therapies to combat age-related cellular damage and disease.
MedicalResearch.com: What are the main findings?
Response: We began by investigating telomere maintenance in laboratory-cultured lines of human embryonic stem cells (ESCs). Using molecular techniques, we varied telomerase activity. Perhaps not surprisingly, cells with too little telomerase had very short telomeres and eventually the cells died. Conversely, cells with augmented levels of telomerase had very long telomeres. But instead of these cells thriving, their telomeres developed instabilities. We also observed that very long telomeres activated trimming mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The lab’s experiments show that reduced expression of these proteins in ESCs prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed responsible for that task.
MedicalResearch.com: What should readers take away from your report?
Response: Ever since researchers connected the shortening of telomeres—the protective structures on the ends of chromosomes—to aging and disease, the race has been on to understand the factors that govern telomere length. We found that a balance of elongation and trimming in stem cells results in telomeres that are, as Goldilocks would say, not too short and not too long, but just right.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The finding, which appears in the December 5, 2016, issue of Nature Structural & Molecular Biology, deepens our understanding of stem cell biology and could help advance stem cell-based therapies, especially related to aging and regenerative medicine. Understanding how telomere length is regulated is an important step toward realizing the promise of these therapies.
MedicalResearch.com: Is there anything else you would like to add?
Response: This work shows that the optimal length for telomeres is a carefully regulated range between two extremes. It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long.
The work was funded by the California Institute for Regenerative Medicine training grant TG2-01158, the Salk Institute Cancer Center Core Grant (P30CA014195), the National Institutes of Health (R01GM087476, R01CA174942), the Highland Street Foundation, the Fritz B. Burns Foundation, the Emerald Foundation and the Glenn Center for Research on Aging.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
A balance between elongation and trimming regulates telomere stability in stem cells
Teresa Rivera, Candy Haggblom, Sandro Cosconati & Jan Karlseder
Nature Structural & Molecular Biology (2016)
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