Molecular and Cell Biology Laboratory
Donald and Darlene Shiley Chair
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.
Left to right:
Liana Goodwin, Daniel Lackner, Makoto Hayashi, Laure Crabbe, Candy Haggblom, Jan Karlseder, Nausica Arnoult, Tony Cesare, Teresa Rivera Garcia, Roddy O'Sullivan
M. Hayashi, A.J. Cesare, T. Rivera, J. Karlseder, Cell death in crisis is mediated by mitotic telomere deprotection. Nature 25;522:492-496, 2015.
N. Arnoult, J. Karlseder, ALT telomere borrow from mitosis to get moving, 2014, Cell, 159 (1), 11-12.
J. Karlseder, Modern genome editing meets telomeres: the many functions of TPP1, 2014, Genes Dev., 28 (17), 1857-1858.
O'Sullivan, R.J., Arnoult, N., Lackner, D.H., Oganesian, L., Haggblom, C., Corpet, A., Almounzi, G. and Karlseder, J. (2014) Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1. Nat Struct Mol Biol 21:167-174.
Cesare, A.J., Hayashi, M.T., Crabbe, L. and Karlseder, J. (2013) The telomere deprotection response is functionally distinct from the genomic DNA damage response. Mol Cell. 51:141-155.
Hayashi, M.T. and Karlseder, J. (2013) DNA damage associated with mitosis and cytokinesis failure. Oncogene. 32:4593-4601.
Lackner, D.H. and Karlseder, J. (2013) C. elegans survivors without telomerase. Worm 2:e21073.
Oganesian, L. and Karlseder, J (2013) 5' C-rich telomeric overhangs are an outcome of rapid telomere truncation events. DNA Repair. 12:238-245.
Barefield, C. and Karlseder, J. (2012) The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures. Nucleic Acids Res 40:7358-7367.
Cesare, A.J. and Karlseder, J. (2012) A three-state model of telomere control over human proliferative boundaries. Curr Opin Cell Biol. 24:731-738.
Crabbe, L., Cesare, A.J., Kasuboski, J.M., Fitzpatrick, J.A. and Karlseder, J. (2012) Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly. Cell Rep. 2:1521-1529.
O'Sullivan, R. and Karlseder, J. (2012) The great unravelling: chromatin as a modulator of the aging process. Trends Biochem Sci. 37:466-476.
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
Targeting telomeres, the timekeepers of cells, could improve chemotherapy
June 24, 2015
Salk's Glenn Center for Aging Research receives an additional $3 million gift from the Glenn Foundation for Medical Research
May 20, 2014
Salk scientists identify factors that trigger ALT-ernative cancer cell growth
January 13, 2014
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
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
Sending out an SOS: How telomeres incriminate cells that can't divide
March 11, 2012
The well-being of living cells requires specialized squads of proteins that maintain order. Degraders chew up worn-out proteins, recyclers wrap up damaged organelles, and-most importantly-DNA repair crews restitch anything that resembles a broken chromosome. If repair is impossible, the crew foreman calls in executioners to annihilate a cell. As unsavory as this last bunch sounds, failure to summon them is one aspect of what makes a cancer cell a cancer cell. Read more>>