B.S., Biology, University of Innsbruck, Austria
Ph.D., Molecular Biology, University of Vienna
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
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.
Awards and Honors
- The V-Foundation Award for Developing Scientists, 2002
- Charles H. Revson Fellowship, 1999
- Human Frontiers Science Program Fellowship, 1997
- European Molecular Biology Organization Fellowship, 1993
Hayashi, M.T., Cesare, A.J., Fitzpatrick, J.A.J., Lazzerini-Denchi, E. and Karlseder, J. (2012) A Telomere Dependent DNA Damage Checkpoint Induced by Prolonged Mitotic Arrest. Nat Struct Mol Biol 19:387-94.
Lackner, D.H., Raices, M., Maruyama, H., Haggblom, C. and Karlseder, J. (2012) Organismal propagation in the absence of a functional telomerase pathway in Caenorhabditis elegans. EMBO J 31:2024-33.
Oganesian, L. and Karlseder, J. (2011) Mammalian 5' C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance. Mol Cell 42:224-236.
Lackner, D., Durocher, D. and Karlseder, J. (2011) A siRNA-based screen for genes involved in chromosome end protection. PLoSONE 6:e21407.
O'Sullivan, R.J., Kubicek, S., Schreiber, S.L. and Karlseder, J. (2010) Reduced histone biosynthesis and chromatin changes aging arising from a damage signal at telomeres. Nat Struct Mol Biol. 17:1218-1225.
O'Sullivan, R.J. and Karlseder, J. (2010) Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 11:171-181.
Raices, M., Verdun, R., Compton, S., Haggblom, C., Griffith, J., Dillin, A. and Karlseder, J. (2008) C. elegans telomeres contain G-strand and C-strand overhangs that are bound by distinct proteins. Cell 132:745-757.
Verdun, R.E. and Karlseder, J. (2007) Replication and protection of telomeres. Nature 447:924-931.
Crabbe, L., Jauch, A., Naeger, C.M., Holtgreve-Grez, H. and Karlseder, J. (2007) Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc Natl Acad Sci USA 104:2205-2210.
Verdun, R.E. and Karlseder, J. (2006) The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127:709-720.
Karlseder, J. (2006) Telomeric proteins: clearing the way for the replication fork. Nat Struct Mol Biol 13:386-387.
Verdun, R.E., Crabbe, L., Haggblom, C. and Karlseder, J. (2005) Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20:551-561.
Raices, M., Maruyama, H., Dillin, A. and Karlseder, J. (2005) Uncoupling of longevity and telomere length in C. elegans. PLoS Genet 1:e30.
Crabbe, L., Verdun, R.E., Haggblom, C.I. and Karlseder, J. (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306:1951-1953.
Salk News Releases
- Critical pathway in cell cycle may lead to cancer development, July 11, 2013
- Chromosome "anchors" organize DNA during cell division, December 20, 2012
- Salk professors awarded chair appointments, August 10, 2012
- Salk scientists open new window into how cancers override cellular growth controls, March 21, 2012
- Sending out an SOS: How telomeres incriminate cells that can't divide, March 11, 2012
- A new ending to an old "tail", April 21, 2011
- Salk Institute promotes latest generation of extraordinary scientists, April 15, 2011
- Ticking of a cellular clock promotes seismic changes in the chromatin landscape associated with aging, October 3, 2010
- How worms protect their chromosomes: Thereby hangs a surprising tail, March 11, 2008
- FISH-ing for links between cancer and aging, February 5, 2007
- DNA repair teams' motto: 'To protect and serve', November 16, 2006
- Tiny roundworm's telomeres help scientists to tease apart different types of aging, August 5, 2005
- Normal chromosome ends elicit a limited DNA damage response, November 22, 2005
- Salk Scientists Provide Insight into Aging, December 9, 2004
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