Early telomerase inactivation accelerates aging independently of telomere length.
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.
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.
Zhengwei
Z
Xie
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Kyle A
KA
Jay
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Dana L
DL
Smith
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.
Yi
Y
Zhang
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.
Zairan
Z
Liu
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.
Jiashun
J
Zheng
Center for Quantitative Biology, School of Physics and The Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Ruilin
R
Tian
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.
Hao
H
Li
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: elizabeth.blackburn@ucsf.edu.
Elizabeth H
EH
Blackburn
D002453:Cell Cycle; D015825:Chromosomes, Fungal / Q000378:metabolism; D004261:DNA Replication; D008928:Mitochondria / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism
D029701:Saccharomyces cerevisiae Proteins; C517042:RNR3 protein, S cerevisiae; D012262:Ribonucleoside Diphosphate Reductase; D019098:Telomerase