The Stowers Institute’s Baumann Lab has discovered an important step in the maturation pathway of telomerase, the enzyme that replenishes the sequences that are lost at chromosome ends with every cell division.
Telomerase is viewed as a promising cancer treatment target because its inhibition selectively kills cancer cells. In order to identify small molecules that block telomerase, it is critical to decipher how the enzyme is made and assembled from its components. Telomerase uses part of an RNA subunit as a template to add telomeric DNA to the ends of chromosomes. The Baumann Lab found that this RNA subunit is first made as a longer inactive form that must be processed into a shorter mature form for telomerase to function.
“We discovered a new pathway of RNA 3’ end (tail end) processing,” said Jeremy Bunch, Research Technician III and co-equal first author on the paper. “The 3’ ends of many RNAs must be processed to produce a mature and functional form. Generally, this involves exonucleolytic degradation, the gradual removal of nucleotides one at a time until the mature end has been reached. Some RNAs are cleaved near the end before exonucleolytic degradation proceeds to generate the mature end. We now show that 3’ end processing for telomerase RNA uses a fundamentally different and novel pathway.”
“We demonstrate that the machinery that removes introns from messenger RNAs also functions in generating the mature 3’ end of the telomerase RNA subunit,” said Jessica Box, Research Technician I and co-equal first author on the paper. “It was highly unexpected that the spliceosome could have such a function, as the two steps of removing an internal piece of RNA and gluing the flanking ends together are tightly coupled during intron removal. To our knowledge this is the first example where uncoupling of the first and second step of splicing generates a functional product in a single-step reaction.”
The work sheds light on human health by demonstrating that interfering with telomerase maturation can inactivate telomerase. Because finding inhibitors for telomerase has been challenging, the identification of a whole set of potential new targets is welcome news for researchers in the Baumann Lab.
“If we can now identify those factors that are specifically required for telomerase processing, we could have new targets for telomerase inhibition in cancer cells,” said Peter Baumann, Ph.D., Assistant Investigator and senior author on the paper. “Defects in the processing machinery for human telomerase are also likely to compromise telomerase function and may thus contribute to diseases such as dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis.”
Weng Tang, a Predoctoral Researcher in the Baumann Lab, also contributed to the paper.
- Box et al. Spliceosomal cleavage generates the 3′ end of telomerase RNA. Nature, December 5, 2008; DOI: 10.1038/nature07584
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