title: Repair of endogenous DNA base lesions modulate lifespan in mice.
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 O(6)-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.
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Lisiane B
authors.initials: LB
authors.lastname: Meira
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Dharini
authors.initials: D
authors.lastname: Shah
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Klapacz
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Moroski-Erkul
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Rodent Histopathology Core, Harvard Medical School, 126 Goldenson Building, Boston, MA 02115, United States.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Biology Department, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States; Rodent Histopathology Core, Harvard Medical School, 126 Goldenson Building, Boston, MA 02115, United States. Electronic address: lsamson@mit.edu.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C528331:MGMT protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; D045643:DNA Repair Enzymes
keywords: AAG/MPG; Aging; Base excision repair; DNA adducts; DNA glycosylase; Mgmt