Salk Institute for Biological Studies

Faculty

Jan Karlseder

Jan Karlseder

Professor
Molecular and Cell Biology Laboratory
Donald and Darlene Shiley Chair

Education

Research

Jan Karlseder, professor in the Molecular and Cell 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.

"Safeguarding the ends of linear chromosomes, known as telomeres, is essential for survival. We are trying to understand how cells keep tabs on their telomeres, how they control cellular proliferation and lifespan and how they regulate the interrelationship of aging and cancer."

Telomeres, the protective ends of chromosomes, become shorter each time cells divide. Often described as the genomic equivalent of the plastic caps that keep shoelaces from fraying, telomeres mask those ends from vigilant repair proteins, which might mistake exposed chromosome ends for broken DNA. When telomeres become critically short and fail to protect the chromosomes, cells cease to grow, or die. On one hand, this process controls cellular and organismal aging by limiting the number of times cells can divide. On the other hand, this limitation on cellular proliferation ensures that cells do not become immortal and therefore represents a powerful tumor suppressive pathway, illustrating the intricate relationship between aging, proliferation and cancer formation.

Karlseder and his group have recently discovered that the relationship between telomeres and cancer extends much further than previously assumed. The group discovered that if cells take too long to undergo cell division, the telomeres send out a molecular SOS signal. These findings have dual implications for cancer therapy. First, they show how a class of anti-cancer drugs that slows cell division—known as mitotic inhibitors— kills cells. This class includes the commonly used chemotherapy drugs vinblastine, Taxol and Velcade. While these drugs have been in use for decades, it was unclear why they actually killed cancer cells. Research from the Karlseder lab has now demonstrated that exposure to mitotic inhibitors causes telomeres to lose their protective function, and the cells respond with stress signals that eventually lead to the death of cancer cells.

Second, these findings suggest ways to make therapies with mitotic inhibitors more potent; novel strategies could be used in combinatorial cancer chemotherapy regimes, which rely on the synergy between two or more drugs. The theory is that a multi-pronged approach might pack more of a wallop than a sledgehammer alone. By providing the link between mitotic inhibition, telomere deprotection and cell death, Karlseder's lab continues to unravel the intricate links between chromosome ends, aging and cancer.

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