Redox Biology (Jul 2018)
Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging
- Andria R. Robinson,
- Matthew J. Yousefzadeh,
- Tania A. Rozgaja,
- Jin Wang,
- Xuesen Li,
- Jeremy S. Tilstra,
- Chelsea H. Feldman,
- Siobhán Q. Gregg,
- Caroline H. Johnson,
- Erin M. Skoda,
- Marie-Céline Frantz,
- Harris Bell-Temin,
- Hannah Pope-Varsalona,
- Aditi U. Gurkar,
- Luigi A. Nasto,
- Renã A.S. Robinson,
- Heike Fuhrmann-Stroissnigg,
- Jolanta Czerwinska,
- Sara J. McGowan,
- Nadiezhda Cantu-Medellin,
- Jamie B. Harris,
- Salony Maniar,
- Mark A. Ross,
- Christy E. Trussoni,
- Nicholas F. LaRusso,
- Eugenia Cifuentes-Pagano,
- Patrick J. Pagano,
- Barbara Tudek,
- Nam V. Vo,
- Lora H. Rigatti,
- Patricia L. Opresko,
- Donna B. Stolz,
- Simon C. Watkins,
- Christin E. Burd,
- Claudette M. St. Croix,
- Gary Siuzdak,
- Nathan A. Yates,
- Paul D. Robbins,
- Yinsheng Wang,
- Peter Wipf,
- Eric E. Kelley,
- Laura J. Niedernhofer
Affiliations
- Andria R. Robinson
- 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
- Matthew J. Yousefzadeh
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Tania A. Rozgaja
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Jin Wang
- Department of Chemistry, University of California, Riverside, CA 92521, USA
- Xuesen Li
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Jeremy S. Tilstra
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
- Chelsea H. Feldman
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA
- Siobhán Q. Gregg
- 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
- Caroline H. Johnson
- The Scripps Research Institute California, La Jolla, CA 92037, USA
- Erin M. Skoda
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Marie-Céline Frantz
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Harris Bell-Temin
- Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Hannah Pope-Varsalona
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Aditi U. Gurkar
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Luigi A. Nasto
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Paediatric Orthopaedics, G. Gaslini Children's Hospital, Genoa, Italy
- Renã A.S. Robinson
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Heike Fuhrmann-Stroissnigg
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Jolanta Czerwinska
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Sara J. McGowan
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Nadiezhda Cantu-Medellin
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Jamie B. Harris
- Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA
- Salony Maniar
- Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Mark A. Ross
- Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Christy E. Trussoni
- Division of Gastroenterology and Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
- Nicholas F. LaRusso
- Division of Gastroenterology and Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
- Eugenia Cifuentes-Pagano
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Patrick J. Pagano
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Barbara Tudek
- 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
- Nam V. Vo
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Lora H. Rigatti
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA
- Patricia L. Opresko
- 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
- Donna B. Stolz
- 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
- Simon C. Watkins
- 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
- Christin E. Burd
- Department of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus OH 43210 USA
- Claudette M. St. Croix
- 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
- Gary Siuzdak
- The Scripps Research Institute California, La Jolla, CA 92037, USA
- Nathan A. Yates
- 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
- Paul D. Robbins
- 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
- Yinsheng Wang
- Department of Chemistry, University of California, Riverside, CA 92521, USA
- Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Eric E. Kelley
- Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV 26506, USA; Correspondence to: West Virginia University School of Medicine, Department of Physiology and Pharmacology, 3072B Health Sciences Center, Morgantown, WV 26506-9229, USA.
- Laura J. Niedernhofer
- 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; Correspondence to: The Scripps Research Institute, Department of Molecular Medicine, 130 Scripps Way #3B3, Jupiter, FL 33458, USA.
- Journal volume & issue
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Vol. 17
pp. 259 – 273
Abstract
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. Keywords: Reactive oxygen species, Free radicals, Genotoxic stress, Oxidative lesions, Endogenous DNA damage, Cellular senescence, Aging
