Telomeres are repetitive nucleotide sequences rich in guanine residues located at the termini of linear chromosomes of eukaryotic organisms. Telomeres function as capping agents to protect chromosomes both from shortening at each replication cycle and from fusing with other chromosome ends or rearranging. Maintenance of telomeres length is critical for genomic stability and cell viability. Telomeres are consumed during cell division but can be replenished by telomerase, a unique ribonucleoprotein enzyme that adds telomeric repeats onto chromosome ends to maintain telomere length. Telomerase uses an RNA template that is integral part of the enzyme and a specialized reverse transcriptase to processively synthesize the G-rich telomeric strand. The importance of the discovery of telomeres and telomerase was recognized by the Nobel Prize award in Physiology or Medicine in 2009.
Telomerase is not active in normal somatic cells, but is highly active in most cancers, and is thus of interest as a target for anticancer drugs. In addition, mutations in both the telomerase RNA and telomerase proteins are associated with some diseases. Human telomerase contains a 451 nt RNA along with a variety of proteins besides the reverse transcriptase. Only a few nucleotides of human telomerase RNA (hTR) are needed as a template to elongate telomeres, but the function the rest of the RNA is unknown. By investigating the structure of the hTR, we will try to shed light to this question.
The aims of the project presented for this fellowship are to determine by X-ray crystallography the three-dimensional structures of separate domains of hTR, the interaction between domains and, ultimately, the structure of the whole hTR alone and/or complexed with a reverse transcriptase protein. The knowledge of the precise three-dimensional structure of hTR and its interaction with telomerase reverse transcriptase is essential to understand its role in telomerase function and how it can be regulated.
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