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      Peroxiredoxins are conserved markers of circadian rhythms

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Cellular life emerged ~3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles due to the Earth’s rotation. The advantage conferred upon organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation-reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterising their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription-translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular time-keeping with redox homeostatic mechanisms following the Great Oxidation Event ~2.5 billion years ago.

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          Most cited references64

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          Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.

          Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. For example, a variety of single amino acid mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis. Knocking out the SOD2 gene in mice results in a lethal cardiomyopathy. A single amino acid mutation in human SOD3 is associated with 10 to 30-fold increases in serum SOD3 levels. As more information is obtained, further insights will be gained.
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            Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling.

            Eukaryotic 2-Cys peroxiredoxins (2-Cys Prxs) not only act as antioxidants, but also appear to regulate hydrogen peroxide-mediated signal transduction. We show that bacterial 2-Cys Prxs are much less sensitive to oxidative inactivation than are eukaryotic 2-Cys Prxs. By identifying two sequence motifs unique to the sensitive 2-Cys Prxs and comparing the crystal structure of a bacterial 2-Cys Prx at 2.2 angstrom resolution with other Prx structures, we define the structural origins of sensitivity. We suggest this adaptation allows 2-Cys Prxs to act as floodgates, keeping resting levels of hydrogen peroxide low, while permitting higher levels during signal transduction.
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              Circadian Clocks in Human Red Blood Cells

              Summary Circadian (~24 hour) clocks are fundamentally important for coordinated physiology in organisms as diverse as cyanobacteria and humans. All current models of the clockwork in eukaryotic cells are based on transcription-translation feedback loops. Non-transcriptional mechanisms in the clockwork have been difficult to study in mammalian systems. We circumvented these problems by developing novel assays using human red blood cells (RBCs), which have no nucleus (or DNA), and therefore cannot perform transcription. Our results show that transcription is, in fact, not required for circadian oscillations in humans, and that non-transcriptional events appear sufficient to sustain cellular circadian rhythms. Using RBCs, we found that peroxiredoxins, highly conserved antioxidant proteins, undergo ~24 hour redox cycles, which persist for many days under constant conditions (i.e. in the absence of external cues). Moreover, these rhythms are entrainable (i.e. tunable by environmental stimuli), and temperature-compensated, both key features of circadian rhythms. We anticipate our findings will facilitate more sophisticated cellular clock models, highlighting the interdependency of transcriptional and non-transcriptional oscillations in potentially all eukaryotic cells.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                7 July 2012
                16 May 2012
                24 November 2012
                : 485
                : 7399
                : 459-464
                Affiliations
                [1 ]Department of Clinical Neurosciences, University of Cambridge Metabolic Research Laboratories, NIHR Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ,UK
                [2 ]Department of Genetics, University of Leicester, Leicester LE1 7RH, UK
                [3 ]Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
                [4 ]Synthetic and Systems Biology (SynthSys), Mayfield Road, EH9 3JD, Edinburgh, UK
                [5 ]School of Biological Sciences, University of Edinburgh, Mayfield Road, EH9 3JR, Edinburgh, UK
                [6 ]Department of Molecular Chronobiology, Center for Life Sciences, University of Groningen, The Netherlands
                [7 ]Institute for Systems Biology, 401 Terry Ave N, Seattle, WA 98109, USA
                [8 ]MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
                Author notes
                [$]

                These authors contributed equally to this work

                [* ]Correspondence Tel: +44 1223 769038 areddy@ 123456cantab.net or jso22@ 123456medschl.cam.ac.uk
                Article
                UKMS47490
                10.1038/nature11088
                3398137
                22622569
                b0022519-42eb-43dc-9580-86a718663f48

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                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 093734 || WT
                Funded by: Wellcome Trust :
                Award ID: 083643 || WT
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