Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.

Autor:	Robinson AR; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Yousefzadeh MJ; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Rozgaja TA; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Wang J; Department of Chemistry, University of California, Riverside, CA 92521, USA., Li X; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Tilstra JS; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Feldman CH; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA., Gregg SQ; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Johnson CH; The Scripps Research Institute California, La Jolla, CA 92037, USA., Skoda EM; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA., Frantz MC; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA., Bell-Temin H; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Pope-Varsalona H; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA., Gurkar AU; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Nasto LA; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Paediatric Orthopaedics, G. Gaslini Children's Hospital, Genoa, Italy., Robinson RAS; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA., Fuhrmann-Stroissnigg H; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Czerwinska J; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland., McGowan SJ; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Cantu-Medellin N; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA., Harris JB; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA., Maniar S; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Ross MA; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Trussoni CE; Division of Gastroenterology and Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA., LaRusso NF; Division of Gastroenterology and Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA., Cifuentes-Pagano E; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Pagano PJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Tudek B; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland., Vo NV; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA., Rigatti LH; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA., Opresko PL; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA., Stolz DB; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Watkins SC; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Burd CE; Department of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus OH 43210 USA., Croix CMS; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Siuzdak G; The Scripps Research Institute California, La Jolla, CA 92037, USA., Yates NA; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Biomedical Mass Spectrometry Center, Schools of the Health Sciences University of Pittsburgh, Pittsburgh, PA 15213, USA., Robbins PD; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA., Wang Y; Department of Chemistry, University of California, Riverside, CA 92521, USA., Wipf P; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA., Kelley EE; Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV 26506, USA. Electronic address: eric.kelley@hsc.wvu.edu., Niedernhofer LJ; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lniedern@scripps.edu.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2018 Jul; Vol. 17, pp. 259-273. Date of Electronic Publication: 2018 Apr 13.
DOI:	10.1016/j.redox.2018.04.007
Abstrakt:	Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1 -/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1 -/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1 -/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1 -/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1 -/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1 -/∆ and aged WT mice. Chronic treatment of Ercc1 -/∆ mice with the mitochondrial-targeted radical scavenger XJB-5-131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline. (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu