Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice

Telomerase is a ribonucleoprotein containing an essential telomerase RNA template and telomerase reverse transcriptase (TERT) that maintains telomeres. The dosage requirements for mammalian TERT in telomere length homeostasis are not known, but are of importance in cellular senescence, stem cell renewal, and cancer. Here, we characterize telomere maintenance and function upon successive breeding of mice deficient in mTert. These studies reveal a unique dosage requirement for telomere length maintenance by TERT; despite haploinsufficiency for the maintenance of long telomeres, mTert+/- mice retain minimal telomere DNA at all chromosome ends and do not exhibit the infertility typical of telomerase-deficient strains. Unlike the long (> 50 kbp) average telomere lengths of wild-type laboratory mice, mTert+/- animals mice possess short telomere lengths similar to humans and wild-derived mice. Unexpectedly, mTert+/- mice are ersatz carriers for genetic instability, because their mating led to accelerated genetic instability and infertility in null progeny. Thus, limiting TERT levels play a key role in the maintenance of genome integrity, with important ramifications for the maintenance of short telomeres in human cancer and aging.