Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes.
Autosomal dominant mutations in telomere-associated factors elicit a disease known as dyskeratosis congenita (DKC), and patients suffer proliferative abnormalities associated with telomere erosion. Mice that are heterozygous for telomerase genes (Tert or Terc, hereafter referred to as mTert and mTerc) are useful models of telomerase haploinsufficiency, but do not strictly mimic DKC. In strains with long telomeres (>60 kbp), animals that are heterozygous for mTert undergo telomere erosion for nine generations and remain phenotypically normal. In an mTerc heterozygous strain with short telomeres (<15 kbp), early mortality arises after five to six generations, but dyskeratosis occurs only upon the further loss of mPot1b. We show that prolonged mTert heterozygosity (for greater than ten generations) did not elicit disease, even upon heterozygote interbreeding, and that telomeres reset to wild-type lengths. This lengthening did not occur in nullizygotes, and short telomeres inherited from mTert null parents were rescued only in heterozygous progeny. In the bone marrow, nullizygotes remained competent for radioprotection for three generations. Thus, gradual telomere erosion in the presence of telomerase may enable subsequent telomere extension, similar to that described in budding yeast. We speculate whether such adaptation occurs in normal human cells (or whether it could be induced in DKC-derived cells), and whether it might mitigate the impact of telomerase inhibition upon stem cells during cancer therapy.
Ontario Cancer Institute/Campbell Family Institute for Cancer Research, Toronto, ON, Canada.
Marie
M
Meznikova
Natalie
N
Erdmann
Rich
R
Allsopp
Lea A
LA
Harrington
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D004195:Disease Models, Animal; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D004718:Saccharomycetales; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000648:ultrastructure*
D019098:Telomerase