Abstract
Components or downstream targets of many signaling pathways such as Insulin/IGF-1 and TOR, as well as genes involved in cellular metabolism and bioenergetics can extend worm lifespan 20% or more. The C. elegans gene pch-2 and its homologs, including TRIP13 in humans, have been studied for their functions in cell mitosis and meiosis, but have never been implicated in lifespan regulation. Here we show that over-expression of TRIP13 in human fibroblasts confers resistance to environmental stressors such as UV radiation and oxidative stress. Furthermore, pch-2 overexpression in C. elegans extends worm lifespan, and enhances worm survival in response to various stressors. Conversely, reducing pch-2 expression with RNAi shortens worm lifespan. Additional genetic epistasis analysis indicates that the molecular mechanism of pch-2 in worm longevity is tied to functions of the sirtuin family, implying that pch-2 is another chromatin regulator for worm longevity. These findings suggest a novel function of the pch-2 gene involved in lifespan determination.
Highlights
The Pachytene CHeckpoint 2 gene has been studied for its functions in monitoring and correcting DNA errors during cell mitosis [1]
Classic genetic and functional genomics screens have identified a number of genes that are involved in C
There are a small proportion of the Insulin/IGF-1 pathway downstream key mediators, such as, DAF-16, SKN-1 and DAF-16-regulated genes including HSF-1 and RPN-6, that extend worm lifespan in over-expressors [18,19,20,21]
Summary
The Pachytene CHeckpoint 2 (pch-2) gene has been studied for its functions in monitoring and correcting DNA errors during cell mitosis [1]. PCH2 and silent information regulator 2 (SIR2) are found predominantly in the nucleolus. Mutation of PCH2, or SIR2, bypasses checkpoint-induced pachytene arrest, and PCH2 and SIR2 are both needed to prevent meiotic interhomolog recombination within the repeated ribosomal RNA genes that are present in the nucleolus [1, 2]. Increased expression of the SIR2 family proteins, called the ‘‘sirtuins,’’ has been shown to enhance lifespan in a range of organisms, including S. cerevisiae, C. elegans, D. melanogaster, and M. musculus. The latest study in brainspecific Sirt1-overexpressing (BRASTO) transgenic mice demonstrated a significant life span extension of
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