Repair of endogenous DNA base lesions modulate lifespan in mice
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 respon...
| Main Authors: | , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2015
|
| Online Access: | http://hdl.handle.net/1721.1/99516 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1811092371173015552 |
|---|---|
| author | Meira, Lisiane B. Calvo, Jennifer A. Shah, Dharini Klapacz, Joanna Moroski-Erkul, Catherine A. Bronson, Roderick T. Samson, Leona D |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Meira, Lisiane B. Calvo, Jennifer A. Shah, Dharini Klapacz, Joanna Moroski-Erkul, Catherine A. Bronson, Roderick T. Samson, Leona D |
| author_sort | Meira, Lisiane B. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:17:06Z |
| format | Article |
| id | mit-1721.1/99516 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:17:06Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/995162022-09-29T13:53:37Z Repair of endogenous DNA base lesions modulate lifespan in mice Meira, Lisiane B. Calvo, Jennifer A. Shah, Dharini Klapacz, Joanna Moroski-Erkul, Catherine A. Bronson, Roderick T. Samson, Leona D 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 Meira, Lisiane B. Calvo, Jennifer A. Shah, Dharini Klapacz, Joanna Moroski-Erkul, Catherine A. Bronson, Roderick T. Samson, Leona D. 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. National Institutes of Health (U.S.) (Grant R01-CA075576) National Institutes of Health (U.S.) (Grant R01-ES022872) National Institutes of Health (U.S.) (Grant R01-CA149261) National Institutes of Health (U.S.) (Grant P30-ES002109) 2015-10-29T18:14:50Z 2015-10-29T18:14:50Z 2014-06 2014-04 Article http://purl.org/eprint/type/JournalArticle 15687864 http://hdl.handle.net/1721.1/99516 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. https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.1016/j.dnarep.2014.05.012 DNA Repair Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Meira, Lisiane B. Calvo, Jennifer A. Shah, Dharini Klapacz, Joanna Moroski-Erkul, Catherine A. Bronson, Roderick T. Samson, Leona D Repair of endogenous DNA base lesions modulate lifespan in mice |
| title | Repair of endogenous DNA base lesions modulate lifespan in mice |
| title_full | Repair of endogenous DNA base lesions modulate lifespan in mice |
| title_fullStr | Repair of endogenous DNA base lesions modulate lifespan in mice |
| title_full_unstemmed | Repair of endogenous DNA base lesions modulate lifespan in mice |
| title_short | Repair of endogenous DNA base lesions modulate lifespan in mice |
| title_sort | repair of endogenous dna base lesions modulate lifespan in mice |
| url | http://hdl.handle.net/1721.1/99516 https://orcid.org/0000-0002-7112-1454 |
| work_keys_str_mv | AT meiralisianeb repairofendogenousdnabaselesionsmodulatelifespaninmice AT calvojennifera repairofendogenousdnabaselesionsmodulatelifespaninmice AT shahdharini repairofendogenousdnabaselesionsmodulatelifespaninmice AT klapaczjoanna repairofendogenousdnabaselesionsmodulatelifespaninmice AT moroskierkulcatherinea repairofendogenousdnabaselesionsmodulatelifespaninmice AT bronsonroderickt repairofendogenousdnabaselesionsmodulatelifespaninmice AT samsonleonad repairofendogenousdnabaselesionsmodulatelifespaninmice |