The Ahmed Lab

Telomeres and Telomerase

Telomeres are simple repetitive sequences at the ends of chromosomes. In most organisms, telomeres are maintained by telomerase, a reverse transcriptase that adds repeats to chromosome termini. Defects in telomerase have been shown to cause the lethal human hereditary disorders Aplastic Anemia and Pulmonary Fibrosis. We have identified a number of C. elegans mutants with defects in telomerase by looking for mortal germline mutants, which become sterile when propagated for several generations. These mutants display progressive telomere erosion and progressive increases in end-to-end chromosome fusions. Studies of C. elegans telomerase mutants may provide insight into how telomerase functions in vivo in multicellular organisms.

Telomerase is deficient in most normal human somatic cells, yet is reactivated in most tumors. When telomeres malfunction in cells deficient for telomerase, they can trigger genome rearrangments, some of which may drive tumorigenesis. We are investigating telomere-induced genome instability using a unique genetic resource: the holocentric chromosomes of C. elegans, which allow us to genetically isolate and study stable end-to-end chromosome fusions that arise when telomerase is deficient.

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Figure 1. a, DAPI-stained oocyte nuclei from some late generation mortal germline mutants reveal fewer than the expected 6 pairs of chromosomes, indicating that chromosome fusions have occurred. b, End-to-end chromosome fusions isolated from mrt-2. c, Telomere length shortens in the mrt-1 and mrt-2 mutants, which are deficient for telomerase in vivo.