Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase that synthesizes telomere sequences do novo onto chromosome ends. Telomerase is specialized reverse transcriptase, requiring both a catalytic protein and an essential RNA component. In the abseces of telomerase, telomeres shorten progressively as cells divide, and telomere function is lost. For this reason, telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. My lab is focused on understanding telomerase and cellular and organismal consequences of telomere dysfunction. We use biochemistry, yeast, and mice to examine telomere function. We generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. We also are using our telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to the stem cell loss. We have developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated.
Kaizer H, Connelly CJ, Bettridge K, Viggiani C, Greider CW. Regulation of Telomere Length Requires a Conserved N-Terminal Domain of Rif2 in Saccharomyces cerevisiae. Genetics. 2015 PMID: 26294668.
Lee SS, Bohrson C, Pike AM, Wheelan SJ, Greider CW. ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells. Cell Rep. 2015 PMID: 26586427.
Wang S, Pike AM, Lee SS, Strong MA, Connelly CJ, Greider CW. BRD4 inhibitors block telomere elongation. Nucleic Acids Res. 2017 PMID: 28854735
Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, Danilova L, Applegate CD, Bolton SG, Mohr DW, Brodsky RA, Casella JF, Greider CW, Jackson JB, Armanios M. Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A. 2018 PMID: 29463756.
Pike AM, Strong MA, Ouyang JPT, Greider CW. TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. Mol Cell Biol. 2019 PMID: 31383750.