Repair of endogenous DNA base lesions modulate lifespan in mice
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Samson_Repair of.pdf
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Author(s)
Meira, Lisiane B.
Calvo, Jennifer A.
Shah, Dharini
Klapacz, Joanna
Moroski-Erkul, Catherine A.
Bronson, Roderick T.
Samson, Leona D
Date Issued
June 2014
Journal
DNA Repair
Publisher
Elsevier
Citation
Meira, Lisiane B., Jennifer A. Calvo, Dharini Shah, Joanna Klapacz, Catherine A. Moroski-Erkul, Roderick T. Bronson, and Leona D. Samson. “Repair of Endogenous DNA Base Lesions Modulate Lifespan in Mice.” DNA Repair 21 (September 2014): 78–86.
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Author's final manuscript
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[superscript 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[superscript −/−] 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.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1016/j.dnarep.2014.05.012
