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Jan Karlseder

 

Jan Karlseder

Jan Karlseder

Associate Professor
Molecular and Cell Biology Laboratory

"Safeguarding the ends of linear chromosomes, known as telomeres, is essential for any animal's survival. We are trying to understand how cells keep tabs on their telomeres and prevent catastrophic meltdowns to gain a better understanding of the interrelationship of aging and cancer."

Normally, telomeres shorten as cells divide, acting as a kind of cellular clock ticking down a cell's age. When they shorten to a critical point, the cell stops growing or dies. In cancer, however, the clock runs backward, and telomeres aberrantly elongate, turning what could be a cellular fountain of youth into a potential malignancy. To achieve immortality, cancer cells either activate telomerase, an enzyme that specifically elongates telomeres, or the so-called ALT (Alternative Lengthening of Telomeres) pathway, which maintains telomeres through a process known as recombination. The majority of human cancers maintain their telomeres through telomerase activation, which has prompted the suggestion that telomerase inhibitors should be able to stop rampantly dividing cancer cells in their tracks. Unfortunately, this hope was dashed when ALT emerged as the dominant pathway. Tumor cells can respond with ALT activation when telomerase is inhibited, rendering telomerase inhibitors ineffective for cancer treatment.

At this point, knowledge about the molecular mechanisms underlying telomerase activation or the ALT pathway is minimal. But recent findings from the Karlseder laboratory suggest that the tiny roundworm C. elegans could be an ideal model to define the molecular mechanism whereby telomeres are maintained through the ALT pathway in worms; the findings could then be expanded to human cancer cells. Karlsleder and his team discovered that C. elegans cells rely on primitive telomeres to protect the integrity of their chromosomes. Unlike mammals, which normally terminate both ends of every chromosome with identical tails, the two tails of worm telomeres are different. Each tail is bound by a distinct protein complex, with one regulating the activity of telomerase, while the other governs ALT. He and his team have already identified the first proteins that are specific for regulation of either telomerase or ALT, providing novel insight into these pathways. The ultimate goal of this study is to isolate specific regulators of telomerase or ALT in worms and humans, which will pave the way for the development of universal inhibitors of cancer growth without the shortcomings of current telomerase inhibitors.

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Left to right
Top/back row: Jan Karlseder, Pepper Stockton, Ramiro Verdun, Roddy O'Sullivan Bottom/front row: Liana Oganesian, Coleen Naeger, Marcela Raices, Candy Haggblom

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Faculty

Jan Karlseder

Jan Karlseder

Associate Professor
Molecular and Cell Biology Laboratory

Jan Karlseder, associate professor in the Regulatory Biology Laboratory, is focusing 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. The Karlseder Laboratory believes 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.

Current research centers on different 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.

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