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Vicki Lundblad

 

Vicki Lundblad

Vicki Lundblad

Professor
Molecular and Cell Biology Laboratory

"I am fascinated by the complex DNA transactions that chromosomes undergo—particularly the types of events that occur at telomeres, the very tips of chromosomes. When these telomere-associated DNA processes start to run out of steam, or conversely become overly active, this can lead to either premature aging or cancer predisposition."

Whether cells have a finite or infinite ability to proliferate is determined by the ends of the chromosomes, called telomeres, which are tended to by a dedicated enzyme called telomerase. In cells where telomerase is inactive, telomeres shorten with each cell division until they become so whittled away that they signal the cell to stop dividing; cells that retain telomerase are able to continue dividing indefinitely.

Although our knowledge of how telomerase is regulated in human cells remains incomplete, researchers do know that there is a telomerase complex, which was first identified in simple single-celled organisms. Lundblad's group discovered the key protein subunit of telomerase in budding yeast, providing the tools to identify its human counterpart. In budding yeast, telomerase consists of three proteins, called Est (for ever shorter telomeres). The Est2 protein, together with a telomerase-dedicated RNA, does the heavy lifting in terms of telomere reconstruction, while Est1 and Est3 help orchestrate the process.

Lundblad's lab is now looking for the proteins that tell telomerase when and how to act, again using budding yeast as the starting point. Earlier, her group found a clue when they showed that a small area on the surface of Est1 acted like molecular Velcro, by attaching Est1 (and thus the rest of the telomerase complex) to a telomere-bound protein, thereby ensuring that yeast cells continuously divide. Simply changing a single amino acid on this site prevented telomerase from reaching the ends of chromosomes, and the telomeres shortened.

Lundblad's group postulates that there must be multiple docking points on the surfaces of the three Est proteins, each performing a distinct regulatory activity. To test this, they are surveying the entire surface of the telomerase complex. So far, her group has identified two additional molecular tethering points, on Est1 and Est3, and they are hot on the trail of the proteins that interact with these two sites.

Lab Photo

Left to right:
John Lubin, Bari Ballew, Michael Killoran, Christine Killoran, Tim Tucey, Vicki Lundblad, Ed Mandell, Margherita Paschini

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Vicki Lundblad

Faculty

Vicki Lundblad

Vicki Lundblad

Professor
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.

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