Molecular and Cell Biology Laboratory
Vicki Lundblad, a Professor in the Molecular and Cell Biology Laboratory, seeks to understand the unique properties of telomeres, the specialized structures found at the ends of linear chromosomes. Telomere function relies on a dedicated enzyme called telomerase, which is responsible for keeping chromosome ends fully elongated. In human cells in which telomerase has been experimental manipulated, the resulting loss of DNA from chromosome ends results in a gradual loss in cell proliferation. Most human tissues have very low levels of telomerase, whereas in cancer cells, telomerase is dramatically up-regulated. Scientists believe that this up-regulation is an essential step in tumor development, and thus, drugs that target telomerase could provide a highly specific anti-cancer therapeutic. Conversely, telomere maintenance may also be a crucial determinant that influences the proliferation of certain tissues during the aging process. Even within the normal human population, variations in telomere length correlate with the onset of certain age-related diseases.
Past work in Lundblad's laboratory pioneered the discovery of genes that encode protein subunits of the telomerase enzyme, using baker's yeast as an experimental model system. Her group has also elucidated a regulatory mechanism for telomerase, by demonstrating that a telomere-bound protein called Cdc13 is responsible for recruiting telomerase to chromosome ends. Lundblad is currently expanding on these studies, through detailed mechanistic analysis of telomerase and Cdc13, as well as the identification and characterization of new genes that make important contributions to telomere biology.
"I am fascinated by the fact that the loss of an extremely small amount of DNA from the tips of chromosomes can dramatically impact the aging process. Understanding how this contributes to a healthy lifespan in humans is a major goal of the research in my laboratory."
During our lifespan, our bodies rely on cell division to replenish our lungs, skin, liver and other organs. However, most human cells cannot proliferate indefinitely. Instead, cells have a "clock" that counts down the number of cell divisions. Once cells in a tissue can no longer divide, the ability to withstand the degenerative aspects of aging declines.
Vicki Lundblad discovered that the molecular basis for this clock resides at the very ends of our chromosomes. These chromosome ends — called telomeres — get nibbled away with each cell division, until they become so short that cells are prevented from dividing further. Although Lundblad first uncovered this process in a simple single-celled organism, subsequent studies by clinicians have shown that whether this telomere clock counts down faster or slower is a contributing factor to age-dependent diseases such as bone marrow failure, pulmonary fibrosis and late-onset diabetes.
However, this clock can be re-set by a telomere-dedicated machine called telomerase which re-elongates telomeres, thereby rescuing them from oblivion. Lundblad's group pioneered the discovery of the components of telomerase, once again using a single-celled organism (baker's yeast). Because the process of cell division is basically the same in baker's yeast and human cells, her laboratory's findings provided the tools for uncovering the components of human telomerase. With telomerase components in hand, this has allowed experiments to determine why the telomere clock might count down faster in some cells. Lundblad postulated that these variations are likely due to be how telomerase finds its way to chromosome ends in order to re-set telomere length. In support of this, her laboratory has made a series of discoveries showing that the surface of telomerase has multiple docking sites that ensure its efficient delivery to chromosome ends. This provides an unexpected insight into how telomerase might be manipulated to promote healthy aging.
Left to right:
Vicki Lundblad, Tim Tucey, Cynthia Reyes, Margherita Paschini, John Lubin Salk
Rao, T., Lubin, J., Armstrong, G.S., Tucey T.M., Lundblad, V. and Wuttke, D.S. (2013). Structure of Est3 reveals a bimodal surface with differential roles in telomere replication. PNAS, in press.
Ballew, B.J. and Lundblad, V. (2013) Multiple genetic pathways regulate replicative senescence in telomerase-deficient yeast. Aging Cell, in 12, 719-727.
Lubin, J., Rao, T., Mandell, E.K., Wuttke, D.S. and Lundblad, V. (2013) Dissecting protein function: an efficient protocol for identifying separation-of-function mutations that encode structurally stable proteins. Genetics, 193, 715-725.
Tucey T.M. and Lundblad, V. (2013). A yeast telomerase complex containing the Est1 recruitment protein is assembled early in the cell cycle. Biochemistry, 52, 1131-1133.
Lubin, J.W., Tucey, T.M. and Lundblad, V. (2012). The interaction between the yeast telomerase RNA and the Est1 protein requires three structural elements. RNA, 18, 1597-604.
Paschini, M., Toro, T.B, Lubin, J.W., Braunstein-Ballew, B., Morris, D.K. and Lundblad, V. (2012). A naturally thermolabile activity compromises genetic analysis of telomere function in Saccharomyces cerevisiae. Genetics, 191, 79-93.
Mandell, E.K., Gelinas, A.D., Wuttke, D.S. and Lundblad, V. (2011). Sequence-specific binding to telomeric DNA is not a conserved property of the Cdc13 DNA binding domain. Biochemistry, 50, 6289-6291.
Paschini, M., Mandell, E.K. and Lundblad, V. (2010). Structure prediction-driven genetics in Saccharomyces cerevisiae identifies an interface between the t-RPA proteins Stn1 and Ten1. Genetics, 185, 11-21.
Lee, J.S., Mandell, E.K., Rao, T., Wuttke, D.S. and Lundblad, V. (2010). Investigating the role of the Est3 protein in yeast telomere replication. Nucleic Acids Res., 38, 2279-2290.
Gao, H., Toro, T.B., Paschini, M., Braunstein-Ballew, B., Cervantes, R.B. and Lundblad, V. (2010). Telomerase recruitment in Saccharomyces cerevisiae is not dependent on Tel1-mediated phosphorylation of Cdc13. Genetics 186, 1147-1159.
Gelinas, A.D., Paschini, M., Reyes, F.E., Héroux, A., Batey, R.T., Lundblad, V., and Wuttke, D.S. (2009). The telomere capping proteins Stn1 and Ten1 are structurally related to RPA32 and RPA14. PNAS 106, 19298-19303.
Lee, J.S., Mandell, E.K., Tucey T.M. Morris, D.K. and Lundblad, V. (2008). The Est3 protein associates with yeast telomerase through an OB-fold domain. Nature Struct. & Mol. Biol. 15, 990-997.
Gao, H., Cervantes, R.B., Mandell, E.K., Otero, J., and Lundblad, V. (2007). RPA-like proteins mediate yeast telomere function. Nature Struct. & Mol. Biol. 14, 208-214.
Salk News Releases
Keeping cells youthful: how telomere-building proteins get drawn into the fold
August 25, 2008
Vicki Lundblad to receive 2008 Pearl Meister Greengard Prize
March 24, 2008
DNA ends: common tool, different job
February 14, 2007
Awards and Honors
- American Cancer Society Junior Faculty Award, 1994
- Michael E. DeBakey, M.D. Excellence in Research Award, 1997
- Ellison Medical Foundation Senior Scholar in Aging Award, 2001
- AACR-NFCR Professorship in Basic Cancer Research, 2002
- NIH MERIT award, National Institute on Aging, 2002
- Fellow of the American Association for the Advancement of Science, 2003
- Pearl Meister Greengard Prize, 2008