Early Telomerase Inactivation Accelerates Aging Independently of Telomere Length

Abstract

SUMMRAY Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even Early after Telomerase Inactivation (ETI), yeast mother cells show transient DNA Damage Response (DDR) episodes, stochastically altered cell cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI occurred well before the population senescence and caused late after telomerase inactivation (LTI). ETI phenotypes were morphologically distinct from LTI senescence, genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells, and that a lack of telomerase accelerates otherwise normal aging.

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