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      Genome integrity and disease prevention in the nervous system

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          Abstract

          This review by McKinnon focuses on the etiology of DNA damage in the nervous system and the multiple DNA repair pathways that maintain genome stability and prevent human neurologic disease.

          Abstract

          Multiple DNA repair pathways maintain genome stability and ensure that DNA remains essentially unchanged over the life of a cell. Various human diseases occur if DNA repair is compromised, and most of these impact the nervous system, in some cases exclusively. However, it is often unclear what specific endogenous damage underpins disease pathology. Generally, the types of causative DNA damage are associated with replication, transcription, or oxidative metabolism; other direct sources of endogenous lesions may arise from aberrant topoisomerase activity or ribonucleotide incorporation into DNA. This review focuses on the etiology of DNA damage in the nervous system and the genome stability pathways that prevent human neurologic disease.

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            Causes and consequences of replication stress.

            Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.
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              An energy budget for signaling in the grey matter of the brain.

              Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%), and glutamate recycling using only 3%. Energy usage depends strongly on action potential rate--an increase in activity of 1 action potential/cortical neuron/s will raise oxygen consumption by 145 mL/100 g grey matter/h. The energy expended on signaling is a large fraction of the total energy used by the brain; this favors the use of energy efficient neural codes and wiring patterns. Our estimates of energy usage predict the use of distributed codes, with
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                15 June 2017
                : 31
                : 12
                : 1180-1194
                Affiliations
                Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
                Author notes
                Article
                8711660
                10.1101/gad.301325.117
                5558921
                28765160
                7fc5324b-4810-479a-9cb5-0403a428f8ca
                © 2017 McKinnon; Published by Cold Spring Harbor Laboratory Press

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 15
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: NS-37956
                Award ID: CA-21765
                Funded by: Cancer Center Support
                Award ID: P30 CA21765
                Funded by: St. Jude Children's Research Hospital , open-funder-registry 10.13039/100007737;
                Categories
                1
                8
                Reviews

                dna damage,nervous system,genome stability,neurodevelopment,neurologic disease

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