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Cell. 2015 Feb 26;160(5):928-939. doi: 10.1016/j.cell.2015.02.002.

Early telomerase inactivation accelerates aging independently of telomere length.

Author information

1
Center for Quantitative Biology, School of Physics and The Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Center for Quantitative Biology, School of Physics and The Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
5
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: haoli@genome.ucsf.edu.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: elizabeth.blackburn@ucsf.edu.

Abstract

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 phenotypes occurred well before the population senescence caused late after telomerase inactivation (LTI). They were morphologically distinct from LTI senescence, were 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.

PMID:
25723167
PMCID:
PMC4496004
DOI:
10.1016/j.cell.2015.02.002
[Indexed for MEDLINE]
Free PMC Article

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