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. Our preliminary 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 ROS may alter telomerase function and thus 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 (e.g. TRX, GSH, SOD, catalase, GPX) have similar effects as peroxiredoxins in human cells.
|Ghosh, Avik K; Rossi, Marie L; Singh, Dharmendra Kumar et al. (2012) RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J Biol Chem 287:196-209|