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Review
, 26 (18), 2001-8

Peroxiredoxins, Gerontogenes Linking Aging to Genome Instability and Cancer

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Review

Peroxiredoxins, Gerontogenes Linking Aging to Genome Instability and Cancer

Thomas Nyström et al. Genes Dev.

Abstract

Age is the highest risk factor known for a large number of maladies, including cancers. However, it is unclear how aging mechanistically predisposes the organism to such diseases and which gene products are the primary targets of the aging process. Recent studies suggest that peroxiredoxins, antioxidant enzymes preventing tumor development, are targets of age-related deterioration and that bolstering their activity (e.g., by caloric restriction) extends cellular life span. This review focuses on how the peroxiredoxin functions (i.e., as peroxidases, signal transducers, and molecular chaperones) fit with contemporary theories of aging and whether peroxiredoxins could be targeted therapeutically in the treatment of age-associated cancers.

Figures

Figure 1.
Figure 1.
Overview of catalysis in typical 2-Cys Prx. Hydrogen peroxide (H2O2) is reduced by the peroxidatic Cys that is oxidized to a sulfenic acid intermediate (C48-SOH in yeast). The nascent R-SOH then condenses with the resolving Cys (C171-SH in yeast) of the other Prx molecule in the Prx dimer to produce a disulfide bond. This bond is subsequently reduced by Trx, thus completing the catalytic cycle. A proportion of Cys-SOH molecules can be further oxidized (hyperoxidation) to the sulfinic acid form (Cys-SOOH) in each catalytic cycle, which inactivates peroxidase activity (Wood et al. 2003b). Srxs reduce the sulfinylated forms of 2-Cys Prxs (Biteau et al. 2003; Woo et al. 2005), which allows Prx to re-enter the catalytic, peroxidatic cycle. The hyperoxidized form of Prx forms oligomers (Hall et al. 2011; Saccoccia et al. 2012) that act as molecular chaperones (i.e., inhibit protein aggregation in vitro) (Jang et al. 2004). The boxes denote three principal Prx activities that may affect genome stability and life span: (1) peroxidase activity reducing the levels of harmful peroxides, (2) hyperoxidation by the “floodgate reaction” allowing peroxide levels to reach local thresholds as a second messenger in signal transduction, and (3) hyperoxidation leading to Prx oligomer formation and molecular chaperone activity. (Trr) Trx reductase.
Figure 2.
Figure 2.
Schematic representation of how CR, through RAS–PKA signaling, sustains yeast Prx catalytic activity. (A) At a high concentration of glucose, leading to a high RAS–cAMP–PKA activity, hydrogen peroxide can activate Yap1/Skn7-dependent transcription of the SRX1 mRNA, but its translation is inhibited by PKA. In the absence of Srx, a large portion of Tsa1 becomes hyperoxidized and inactivated. (B) During CR, Ras–PKA activity is reduced, and this relieves the translational inhibition of the SRX1 mRNA in a Gcn2-dependent manner to provide more Srx1 protein and, as a consequence, more reduced peroxidase-active Tsa1. Conditional mutations in Cdc25 reduce Ras activity, create a phenocopy of CR, and extend life span in a Tsa1-dependent manner (Molin et al. 2011).

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