To investigate if ROS indeed perturb telomere length, we have utilized a mutant strain deficient in a peroxiredoxin, namely Tsa1. Tsa1 is one of the major scavengers for ROS in S. cerevisiae. Using a yeast strain defective in Tsa1, we have investigated the effect of defective ROS detoxification on telomere DNA, telomerase, telomere binding proteins, and telomere length. Our observation suggests that ablation of Tsa1 function leads to an increase in ROS level, and also causes abnormal telomere addition. Although the tsa1 mutant has normal telomerase expression and activity, it displays abnormal telomerase-mediated repeat addition at telomere DNA. Furthermore, Tsa1 deficiency can interfere with pathways that are critical in modulating telomerase. These results support that defective ROS scavenging can interfere with pathways that are critical in controlling telomere length homeostasis. Interestingly, the telomere length phenotypes in the mutant budding yeast recapitulate those reported in humans exposed to oxidative environment, but our studies provide mechanistic explanations and therefore serve as useful guidelines for our future studies using mammalian models. For the long-term plan, we will extend this work to human cells deficient in peroxiredoxins. We will also explore if disruptions of other ROS detoxification enzymes have similar effects as peroxiredoxins in human cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000749-02
Application #
8736609
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2013
Total Cost
$76,704
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Lu, Jian; Vallabhaneni, Haritha; Yin, Jinhu et al. (2013) Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis. Aging Cell 12:635-44