In all eukaryotic cells, chromosome ends are capped by protein-DNA structures called telomeres (shown in red at right). Much like the small piece of plastic at the end of a shoelace (called an agnet) which serves to prevent the lace from unraveling, telomeres help to maintain the structural integrity of chromosomes. The primary function of telomeres is to differentiate natural chromosome ends from random DNA breaks. Failure to do so can result in dangerous inter-chromosome fusion events, leading to genomic instability.
Several decades ago, the laboratory of Elizabeth Blackburn identified an enzymatic activity capable of supporting de novo telomere DNA synthesis, which they named telomerase. Subsequently, telomerase was shown to be a ribonucleoprotein (RNP) complex, comprised of a catalytic reverse transcriptase protein subunit, the telomerase RNA, and several additional protein cofactors.
The discovery of the telomerase enzyme provided an elegant solution to the 'End Replication Problem', which arises due to the inability of conventional DNA replication machinery to complete the synthesis of the lagging-strand chromosome during semi-conservative replication. (click here for animation).
In the absence of telomerase, telomere length reduces with every round of cell division. Interestingly, ectopic expression of the telomerase reverse transcriptase protein can combat this telomere attrition and is sufficient to render certain laboratory cell lines immortal. This observation lead researchers to propose a scenario wherein the gradual shortening of telomeres in telomerase deficient cells may function as a ‘molecular clock’, providing a signal which limits the proliferative capacity of cells. This notion has garnered further support from the demonstration that telomere length is maintained via telomerase activation in the majority of human cancers, raising the intriguing possibility that telomerase detection and inhibition may prove useful in cancer diagnosis and treatment, respectively.
The Stone Research Group seeks to further characterize the structural properties of the telomerase RNP as well as the physical basis for telomere length regulation.
We are currently targeting several broad areas of inquiry:
How are individual protein and RNA components assembled into a functional telomerase enzyme?
What are the unique structural properties of the telomerase RNP and what is the role of RNA in promoting catalysis?
How do telomere-associated proteins remodel telomere DNA structure and regulate telomerase activity?