TY - JOUR
T1 - Repair of endogenous DNA base lesions modulate lifespan in mice
AU - Meira, Lisiane B.
AU - Calvo, Jennifer A.
AU - Shah, Dharini
AU - Klapacz, Joanna
AU - Moroski-Erkul, Catherine A.
AU - Bronson, Roderick T.
AU - Samson, Leona D.
N1 - Funding Information:
The authors thank Jonathan Brasher for help in the initial stages of this project. We thank Axel Nohturfft for assistance in writing the R code for the Fisher's exact test. We thank Dr. Edelman for the Exo1 −/− and Msh6 −/− mice. We acknowledge The Hope Babette Tang Histology Facility at MIT's David H. Koch Institute for Integrative Cancer Research, especially Alicia Caron (NCI P30-CA14051). LDS is an ACS Research Professor and the research was supported by NIH grants R01-CA075576, R01-ES022872, R01-CA149261, and P30-ES002109 .
PY - 2014/9
Y1 - 2014/9
N2 - 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.
AB - 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.
KW - AAG/MPG
KW - Aging
KW - Base excision repair
KW - DNA adducts
KW - DNA glycosylase
KW - Mgmt
UR - http://www.scopus.com/inward/record.url?scp=84905406303&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2014.05.012
DO - 10.1016/j.dnarep.2014.05.012
M3 - Article
C2 - 24994062
AN - SCOPUS:84905406303
SN - 1568-7864
VL - 21
SP - 78
EP - 86
JO - DNA Repair
JF - DNA Repair
ER -