Short telomeres initiate telomere recombination in primary and tumor cells.
Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase-some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR-/- and Emumyc+mTR-/-) and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomere length distribution outliers, CO-FISH, Q-FISH, and multicolor FISH to detect subtelomeric recombination. Telomere length was maintained during long-term growth in vivo and in vitro. Long telomeres, characteristic of human ALT cells, were not observed in either late passage or mTR-/- tumor cells; instead, we observed only minimal changes in telomere length. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that length maintenance is due to telomeric recombination. We also detected telomere length changes in primary mTR-/- cells that had short telomeres. Using mouse mTR+/- and human hTERT+/- primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms, including recombination, occurs in primary cells and is initiated by short telomeres, even in the presence of telomerase. Most intriguing, our data indicate that some non-telomerase telomere maintenance mechanisms occur without a significant increase in telomere length.
Morrish
Tammy A
TA
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Greider
Carol W
CW
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008223:Lymphoma / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011995:Recombination, Genetic; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D019098:Telomerase