title: Telomerase suppresses formation of ALT-associated single-stranded telomeric C-circles.
abstract: Telomere maintenance is an essential characteristic of cancer cells, most commonly achieved by activation of telomerase. Telomeres can also be maintained by a recombination-based mechanism, alternative lengthening of telomeres (ALT). Cells using ALT are characterized by the presence of ALT-associated promyelocytic leukemia (PML) bodies (APB), long, heterogeneously sized telomeres, extrachromosomal telomeric circular DNA, and elevated telomeric recombination. Consistent with other reports, we found that liposarcomas containing APBs, but lacking telomerase expression, always contained C-rich circles (C-circles), and these C-circles were never present in the absence of APBs, indicating a tight link between these features in ALT cells. However, a rare subgroup of tumors showing evidence of telomere maintenance by both telomerase and ALT did not contain C-circles. To test the hypothesis that telomerase expression disrupts the tight link between APBs and C-circles, we used ALT cell lines that were engineered to express telomerase. Introduction of telomerase activity in these ALT cells resulted in, on average, shorter telomeres with retention of APBs. However, at high passage, the level of C-circles was significantly reduced, which was paralleled by a switch from C-strand overhangs to G-strand overhangs. We propose that by extending critically short telomeres in these cells, telomerase is disrupting a key step in the ALT pathway necessary for production and/or maintenance of C-circles.
authors.affiliation: Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia 31404, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Plantinga
authors.forename: Kara M
authors.initials: KM
authors.lastname: Pascarelli
authors.forename: Anna S
authors.initials: AS
authors.lastname: Merkel
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.forename: Dominique
authors.initials: D
authors.lastname: Broccoli
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008954:Models, Biological; D009690:Nucleic Acid Conformation; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism
chemical_list: D035321:Telomeric Repeat Binding Protein 1; D019098:Telomerase