Repair of endogenous DNA base lesions modulate lifespan in mice |
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| Affiliation: | 1. Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States;2. Biology Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States;3. Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States;4. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States;5. Rodent Histopathology Core, Harvard Medical School, 126 Goldenson Building, Boston, MA 02115, United States;1. Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China;2. Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China;3. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China;4. Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China;5. Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China;6. Department of Pathology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China;1. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;2. Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas;3. Section of Gastrointestinal Cancer, Division of Cancer Studies, King’s College, London, UK;1. INSERM, UMR_S1165, Paris, France;2. Université Paris Diderot, Department of Pathology, UMR_S1165, Paris, France;3. Centre Hospitalier Universitaire de Caen, Department of Dermatology, Caen, France;4. Université de Caen Basse-Normandie, Medical School, Caen, France;5. Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Department of Pathology, Paris, France;6. Centre Hospitalier Universitaire de Caen, Department of Pathology, Caen, France;2. ETC Education & Training Consultancy, London, United Kingdom;3. Postgraduate Medical Education Centre, Croydon University Hospital, London, United Kingdom;1. Department of Dermatology, Charité Universitätsmedizin, Berlin, Germany;2. Innovation R&D Direction, Laboratoires Expanscience, Epernon, France;3. Department of Dermatology, University of Modena and Reggio Emilia, Italy;4. Department of Dermatology, Institut Alfred Fournier, Paris, France;5. CTIBIOTECH, Lyon, France;6. Department of Dermatology and Venereology, Trakia University-Stara Zagora, Bulgaria;7. Clinreal, Toulouse, France;1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, United States;2. Department of Chemistry, The Scripps Research Institute, Jupiter, FL, United States;3. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, United States;4. Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL, United States;5. Department of Pharmaceutical Sciences, Western New England University, Springfield, MA, United States |
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| Abstract: | The accumulation of DNA damage is thought to contribute to the physiological decay associated with the aging process. Here, we report the results of a large-scale study examining longevity in various mouse models defective in the repair of DNA alkylation damage, or defective in the DNA damage response. We find that the repair of spontaneous DNA damage by alkyladenine DNA glycosylase (Aag/Mpg)-initiated base excision repair and O6-methylguanine DNA methyltransferase (Mgmt)-mediated direct reversal contributes to maximum life span in the laboratory mouse. We also uncovered important genetic interactions between Aag, which excises a wide variety of damaged DNA bases, and the DNA damage sensor and signaling protein, Atm. We show that Atm plays a role in mediating survival in the face of both spontaneous and induced DNA damage, and that Aag deficiency not only promotes overall survival, but also alters the tumor spectrum in Atm−/− mice. Further, the reversal of spontaneous alkylation damage by Mgmt interacts with the DNA mismatch repair pathway to modulate survival and tumor spectrum. Since these aging studies were performed without treatment with DNA damaging agents, our results indicate that the DNA damage that is generated endogenously accumulates with age, and that DNA alkylation repair proteins play a role in influencing longevity. |
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| Keywords: | AAG/MPG Mgmt DNA adducts DNA glycosylase Aging Base excision repair |
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