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Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.

ABSTRACT: This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to various extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression.

SUBMITTER: Perry JJ

PROVIDER: S-EPMC1904427 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.

Perry J J P JJ Fan L L Tainer J A JA

Neuroscience 20061215 4

This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. ...[more]

PMID: 17174478

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Project description:BACKGROUND:Although telomerase has potential for age-related disease intervention, the overexpression of telomerase in about 90% of cancers, and in HIV virus reservoirs, cautions against se in anti-aging telomerase therapeutics. While multiple reviews document the canonical function of telomerase for maintenance of telomeres, as well as an increasing numbers of reviews that reveal new non-canonical functions of telomerase, there was no systematic review that focuses on the array of associates of the subunit of Telomerase Reverse transcriptase protein (TERT) as pieces of the puzzle to assemble a picture of the how specific TERT complexes uniquely impact aging and age-related diseases and more can be expected. METHODS:A structured search of bibliographic data on TERT complexes was undertaken using databases from the National Center for Biotechnology Information Pubmed with extensive access to biomedical and genomic information in order to obtain a unique documented and cited overview of TERT complexes that may uniquely impact aging and age-related diseases. RESULTS:The TERT associations include proper folding, intracellular TERT transport, metabolism, mitochondrial ROS (Reactive Oxygen Species) regulation, inflammation, cell division, cell death, and gene expression, in addition to the well-known telomere maintenance. While increase of cell cycle inhibitors promote aging, in cancer, the cell cycle check-point regulators are ambushed in favor of cell proliferation, while cytoplasmic TERT protects a cell cycle inhibitor in oxidative stress. The oncogene cMyc regulates gene expression for overexpression of TERT, and reduction of cell cycle inhibitors-the perfect storm for cancer promotion. TERT binds with the oncogene RMRP RNA, and TERT-RMRP function can regulate levels of that oncogene RNA, and TERT in a TBN complex can regulate heterochromatin. Telomerase benefit and novel function in neurology and cardiology studies open new anti- aging hope. GV1001, a 16 amino acid peptide of TERT that associates with Heat Shock Proteins (HSP's), bypasses the cell membrane with remarkable anti disease potential. CONCLUSIONS:TERT "associates" are anti-cancer targets for downregulation, but upregulation in antiaging therapy. The overview revealed that unique TERT associations that impact all seven pillars of aging identified by the Trans-NIH Geroscience Initiative that influence aging and urge research for appropriate targeted telomerase supplements/ stimulation, and inclusion in National Institute on Aging Intervention Testing Program. The preference for use of available "smart drugs", targeted to only cancer, not off-target anti- aging telomerase is implied by the multiplicity of TERT associates functions.

Dataset Information

Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.

Publications

Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.

Similar Datasets

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