Co-workers:

 All eukaryotes that possess linear chromosomes require a mechanism to maintain a reserve of non-coding DNA at the extreme chromosomal terminus, called the telomere. Depletion of telomere DNA during cell division, a natural consequence of genome replication, eventually curtails the viability and proliferation of normal and cancerous cells. Telomere depletion is mitigated by telomerase, an enzyme that is comprised of two essential subunits: the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC) that provides the template for new telomere DNA synthesis. In recent years, our research has sought to address the impact of partial or complete loss of telomerase (TERT) function in a physiological context that more closely resembles that of human stem cells; that is, when telomeres are initially longer. In genetic model systems, we have uncovered distinct cellular responses to partial or complete loss of telomerase function that vary from induction of alternate modes of telomere maintenance (such as recombination), to a compensatory increase in telomere length in cells that retain low levels of telomerase activity. We are also interested in the cell signaling mechanisms that are induced by critically short telomeres, alone or when combined with other genotoxic insults such as irradiation and DNA damage. Taken together, we aim to uncover mechanisms by which modulation of telomerase function can be used to alleviate age-associated diseases that may be exacerbated by loss of telomere function.

Selected publications:

Lebel, C., Rosonina, E., Sealey, D.C., Pryde, F., Lydall, D., Maringele, L., and Harrington, L.A. (2009). Telomere maintenance and survival in saccharomyces cerevisiae in the absence of telomerase and RAD52. Genetics 182, 671-684.

Meznikova, M., Erdmann, N., Allsopp, R., and Harrington, L.A. (2009). Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes. Dis Model Mech 2, 620-626.

Sealey, D.C., Zheng, L., Taboski, M.A., Cruickshank, J., Ikura,M., and Harrington, L.A. (2010). The N-terminus of hTERT contains a DNA-binding domain and is required for telomerase activity and cellular immortalization. Nucleic Acids Res 38, 2019-
2035.