Lea Harrington’s team seeks to demystify the mechanisms underlying telomere maintenance and fidelity. It is particularly interested in the enzyme called telomerase (TERT: telomerase reverse transcriptase), and its dosage sensitivity to factors that act to protect telomeres and genome integrity.
Telomeres are highly repetitive DNA sequences that serve as critical caps, analogous to shoelaces, to protect the ends of chromosomes against degradation, fraying, and fusion with other chromosomes.
In most eukaryotes, telomerase maintains and adds new telomeres to chromosomes. The amount and/or activity of this enzyme varies greatly depending on the type of cell. Its activity is present in stem cells as well as in cancer cells, contributing to their immortality, while it is weakly active or absent in most adult cells, thereby contributing to a non-proliferative state called senescence.
As the Harrington group and others have shown, even half of the telomerase activity may be insufficient to maintain telomeres. This telomerase deficiency is now known to explain many human diseases associated with shorter telomeres, called telomeropathies. Affected patients suffer from diseases that include cancer, pulmonary fibrosis, anemia, bone marrow failure and premature mortality.
Not surprisingly, therefore, cancers often subvert the consequences of a telomerase-limiting function by up-regulating TERT. Indeed, mutations within the TERT promoter that up-regulate its expression constitute one of the most common non-coding mutations in cancer. Harrington and others have shown that telomerase inhibition is an effective means of killing cancer cells. Even cancer cells with initially long telomeres succumb to cell death after extensive telomere erosion. For this reason, telomerase remains a potential target for the development of inhibitors against cancer.
Lea Harrington and her team use a variety of cell models, from mammals to yeast, to explain the mechanisms by which cells rely on telomere maintenance for survival. They demonstrated that elongated telomeres delay, but do not circumvent, the potential loss of telomere integrity when telomerase is inhibited.
They are studying the genetic mechanisms that may increase sensitivity to or accelerate telomere instability in cancer cells. They also use genetic approaches to understand how telomere integrity affects the senescence of cells and tissues.
Recently, they uncovered a new link between short telomeres and DNA/histone methylation status elsewhere in the genome, and showed that short telomeres led differentiated cells to adopt a more pluripotent state. These results may have important implications for aging and cancer treatment in contexts in which telomere status is compromised.
Genomics & Epigenetics