Telomerase and the Consequences of Telomere Dysfunction(Nobel Prize 2009)

Nobel laureate Carol Greider, Ph.D., presents the seventh annual Jeffrey M. Trent Lectureship in Cancer Research

Carol Greider lab is interested in telomere function, the regulation of telomere length and the biochemistry of telomerase. Telomeres are essential for both chromosome stability and for length maintenance. Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes telomere repeats onto chromosome ends. Telomerase is required for telomerase length maintenance: in the absence of telomerase, telomeres shorten progressively.

To understand the telomerase, we initially focused on the well characterized Tetrahymena enzyme. We extensively characterized the functional regions of the Tetrahymena telomerase RNA. Using a reconstitution system, we mapped the essential RNA functional region. To extend this analysis to mammalian telomerase we established the secondary structure of the vertebrate telomerase RNA. We cloned and sequenced telomerase RNA genes from 35 vertebrate species and determined the secondary structure using phylogenetic comparative analysis. We identified four highly conserved domains in the RNA structure and found that the global architecture is conserved from Tetrahymena to human. We are currently analyzing the function of these regions in human and mouse telomerase enzyme.

To understand how telomere functions to provide chromosome stability and how telomerase might play a role in cancer, we generated a telomerase null mouse. Mice that lack the gene encoding the mouse Telomerase RNA (mTR) show progressive telomere shorting during successive breeding. The mice are viable for up to six generations although in the later generations there is severe reduction in fertility due to apoptosis in the germ cells. Crosses of these telomerase null mice to other tumor prone mouse models suggest that under some circumstances tumor formation can be greatly reduced when telomerase is absent. This suggests that telomerase inhibition may be a useful approach to cancer treatment. However when both telomerase and p53 are deleted, an increase in tumor formation is seen. This suggests that the loss of telomerase contributes to genomic instability and may cooperate with loss of p53 in tumor initiation. We tested whether the absence of telomerase increases genetic instability by examining the mutation rate in the absence of telomerase in yeast. We found an increase in terminal deletions and the structure of chromosomes resembled the nonreciprical translocations that are frequently found in human tumors. Thus analysis of chromosome rearrangments in yeast will allow us to dissect the genetic requirements of chromosome stability.

We are using the mTR-/- mice to understand the cellular events that occur when telomere function is lost. Germ cell apoptosis in mTR-/- mice is triggered by short telomeres at the onset of meiosis. Evidence suggests that loss of telomere function leads to a DNA damage checkpoint and subsequent apoptosis. We have ongoing experiments designed to study how a cell recognizes a dysfunctional telomere as DNA Damage.

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