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

Authors

• Andria R. Robinson, University of Pittsburgh
• Matthew J. Yousefzadeh, The Scripps Research Institute
• Tania A. Rozgaja, The Scripps Research Institute
• Jin Wang, University of California
• Xuesen Li, The Scripps Research Institute
• Jeremy S. Tilstra, University of Pittsburgh
• Chelsea H. Feldman, University of Pittsburgh
• Siobhan Q. Gregg, University of Pittsburgh
• Caroline H. Johnson, The Scripps Research Institute California
• Erin M. Skoda, University of Pittsburgh
• Marie-Celine Frantz, University of Pittsburgh
• Harris Bell-Temin, University of Pittsburgh
• Hannah Pope-Varsalona, University of Pittsburgh
• Aditi U. Gurkar, The Scripps Research Institute
• Luigi A. Nasto, University of Pittsburgh
• Rena A.S. Robinson, University of Pittsburgh
• Heike Fuhrmann-Stroissnigg, The Scripps Research Institute
• Jolanta Czerwinska, Polish Academy of Sciences
• Sara J. McGowan, The Scripps Research Institute
• Nadiezhda Cantu-Madellin, University of Pittsburgh
• Jamie B. Harris, The Scripps Research Institute
• Salony Maniar, University of Pittsburgh
• Mark A. Ross, University of Pittsburgh
• Christy E. Trussoni, Mayo Clinic
• Nicholas F. LaRusso, Mayo Clinic
• Eugenia Cifuentes-Pagano, University of Pittsburgh
• Patrick J. Pagano, University of Pittsburgh
• Barbara Tudek, Polish Academy & University of Warsaw
• Nam V. Vo, University of Pittsburgh
• Lora H. Rigatti, University of Pittsburgh
• Patricia L. Opresko, University of Pittsburgh
• Donna B. Stolz, University of Pittsburgh
• Simon C. Watkins, University of Pittsburgh
• Christin E. Burd, The Ohio State University
• Claudette M. St, Croix, University of Pittsburgh
• Gary Siuzdak, The Scripps Research Institute California
• Nathan A. Yates, University of Pittsburgh
• Paul D. Robbins, University of Pittsburgh
• Yinsheng Wang, University of California
• Peter Wipf, University of Pittsburgh
• Eric E. Kelley, West Virginia UniversityFollow
• Laura J. Neidernhofer, University of Pittsburgh

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https://orcid.org/0000-0002-5298-1299

https://orcid.org/0000-0001-5153-5011

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https://orcid.org/0000-0003-3291-9911

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Document Type

Article

Publication Date

2018

College/Unit

School of Medicine

Department/Program/Center

Medicine

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-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/Δ 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-/Δ and aged WT mice. Chronic treatment of Ercc1-/Δ 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.

Digital Commons Citation

Robinson, Andria R.; Yousefzadeh, Matthew J.; Rozgaja, Tania A.; Wang, Jin; Li, Xuesen; Tilstra, Jeremy S.; Feldman, Chelsea H.; Gregg, Siobhan Q.; Johnson, Caroline H.; Skoda, Erin M.; Frantz, Marie-Celine; Bell-Temin, Harris; Pope-Varsalona, Hannah; Gurkar, Aditi U.; Nasto, Luigi A.; Robinson, Rena A.S.; Fuhrmann-Stroissnigg, Heike; Czerwinska, Jolanta; McGowan, Sara J.; Cantu-Madellin, Nadiezhda; Harris, Jamie B.; Maniar, Salony; Ross, Mark A.; Trussoni, Christy E.; LaRusso, Nicholas F.; Cifuentes-Pagano, Eugenia; Pagano, Patrick J.; Tudek, Barbara; Vo, Nam V.; Rigatti, Lora H.; Opresko, Patricia L.; Stolz, Donna B.; Watkins, Simon C.; Burd, Christin E.; Croix, Claudette M. St,; Siuzdak, Gary; Yates, Nathan A.; Robbins, Paul D.; Wang, Yinsheng; Wipf, Peter; Kelley, Eric E.; and Neidernhofer, Laura J., "Spontaneous DNA damage to the nuclear genome promotes senescence, T redox imbalance and aging" (2018). Faculty & Staff Scholarship. 1542.
https://researchrepository.wvu.edu/faculty_publications/1542

Source Citation

Robinson, A. R., Yousefzadeh, M. J., Rozgaja, T. A., Wang, J., Li, X., Tilstra, J. S., Feldman, C. H., Gregg, S. Q., Johnson, C. H., Skoda, E. M., Frantz, M.-C., Bell-Temin, H., Pope-Varsalona, H., Gurkar, A. U., Nasto, L. A., Robinson, R. A. S., Fuhrmann-Stroissnigg, H., Czerwinska, J., McGowan, S. J., … Niedernhofer, L. J. (2018). Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biology, 17, 259–273. https://doi.org/10.1016/j.redox.2018.04.007

Comments

© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).