Associate Professor Kathleen Collins

Department of Molecular and Cell Biology

Dr. Collins' laboratory studies ribonucleoproteins (RNPs), with particular focus on the reverse transcriptase telomerase. Telomerase adds one strand of telomeric DNA simple sequence repeats to chromosome ends by copying a template within its integral RNA component. This de novo telomeric repeat addition is required to balance the loss of repeats that occurs with incomplete replication of linear chromosome ends by conventional DNA-dependent DNA polymerases. Cells that do not produce active telomerase, including most cells in multicellular organisms, lose telomeric repeats with each round of cell division. When telomeric repeat number reaches a critical minimum, short telomeres somehow signal for cell death or an irreversible proliferative senescence. Cancer cells escape this limitation by activating telomerase. Telomerase is studied both in vitro, to understand the structure and biochemical mechanisms of this novel reverse transcriptase, and in vivo, to define its cellular roles and regulations. Dr. Collins' research investigates also the structure and function in other RNPs with cellular activities that, like telomerase, may depend intimately on both protein and non-coding (nc) RNA. Recent studies have also involved research on the role of telomerase in aging.

Currently, Dr. Collins' laboratory investigates telomerase in the ciliate Tetrahymena and human cells using techniques from structural biology and enzymology to cell biology and genetics. Some of these studies focus on the protein-nucleic acid interactions that establish the unique features of the telomerase enzyme. For example, the telomerase RNP must distinguish a short sequence within the much larger telomerase RNA as the template for reverse transcription. Also, as substrates for elongation, telomerase must be recruited to authentic chromosome ends but not random DNA breaks. Both of these specificities can be partially recapitulated with recombinant enzyme and are likely to be enhanced by as yet uncharacterized factors as well. Recombinant telomerase proteins and RNAs are used to study the roles of these molecules. Affinity purification techniques are being developed to identify new telomerase components and to investigate a diversity of factors that regulate telomerase function in the cell.

Although much is known about protein folding and RNA folding independently, the principles governing co-folding of protein and RNA in vivo remain unknown. Therefore, Dr. Collins' laboratory also investigates the process of RNP assembly. This research attempts to identify proteins involved in telomerase RNA processing and RNP assembly. This research has led to the discovery that the human telomerase complex includes a set of four proteins shared with a family of RNPs that catalyze ribosomal RNA modification. One of these proteins was initially identified as the gene product of the locus mutant in X-linked dyskeratosis congenita (DKC). Telomerase deficiency can completely account for the DKC disease phenotypes. Dr. Collins' laboratory studies how telomerase is affected by DKC gene mutations and how telomerase in normal and DKC cells is regulated during cellular differentiation, oncogenesis, and aging.