Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1
Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/79393 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1811093137442996224 |
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| author | Calvo, Jennifer A. Moroski-Erkul, Catherine A. Lake, Annabelle Eichinger, Lindsey Wood Shah, Dharini Jhun, Iny Limsirichai, Prajit Bronson, Roderick T. Christiani, David C. Meira, Lisiane B. Samson, Leona D. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Calvo, Jennifer A. Moroski-Erkul, Catherine A. Lake, Annabelle Eichinger, Lindsey Wood Shah, Dharini Jhun, Iny Limsirichai, Prajit Bronson, Roderick T. Christiani, David C. Meira, Lisiane B. Samson, Leona D. |
| author_sort | Calvo, Jennifer A. |
| collection | MIT |
| description | Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage. |
| first_indexed | 2024-09-23T15:40:18Z |
| format | Article |
| id | mit-1721.1/79393 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:40:18Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/793932022-10-02T03:17:42Z Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 Calvo, Jennifer A. Moroski-Erkul, Catherine A. Lake, Annabelle Eichinger, Lindsey Wood Shah, Dharini Jhun, Iny Limsirichai, Prajit Bronson, Roderick T. Christiani, David C. Meira, Lisiane B. Samson, Leona D. Massachusetts Institute of Technology. Department of Biological Engineering Calvo, Jennifer A. Moroski-Erkul, Catherine A. Lake, Annabelle Eichinger, Lindsey Wood Shah, Dharini Jhun, Iny Limsirichai, Prajit Meira, Lisiane B. Samson, Leona D. Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage. National Institutes of Health (U.S.) (NIH grant R01-CA075576) National Institutes of Health (U.S.) (NIH grant R01-CA055042) National Institutes of Health (U.S.) (NIH grant R01-CA149261) National Institutes of Health (U.S.) (NIH grant P30-ES00002) National Institutes of Health (U.S.) (NIH grant P30-ES02109) National Center for Research Resources (U.S.) (grant number M01RR-01066) National Center for Research Resources (U.S.) (grant number UL1 RR025758, Harvard Clinical and Translational Science Center) 2013-07-01T16:46:59Z 2013-07-01T16:46:59Z 2013-04 2013-01 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-734X http://hdl.handle.net/1721.1/79393 Calvo, Jennifer A., Catherine A. Moroski-Erkul, Annabelle Lake, Lindsey W. Eichinger, Dharini Shah, Iny Jhun, Prajit Limsirichai, et al. Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1. Edited by Samuel H. Wilson. PLoS Genetics 9, no. 4 (April 4, 2013): e1003413. https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.1371/journal.pgen.1003413 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Calvo, Jennifer A. Moroski-Erkul, Catherine A. Lake, Annabelle Eichinger, Lindsey Wood Shah, Dharini Jhun, Iny Limsirichai, Prajit Bronson, Roderick T. Christiani, David C. Meira, Lisiane B. Samson, Leona D. Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title | Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title_full | Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title_fullStr | Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title_full_unstemmed | Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title_short | Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1 |
| title_sort | aag dna glycosylase promotes alkylation induced tissue damage mediated by parp1 |
| url | http://hdl.handle.net/1721.1/79393 https://orcid.org/0000-0002-7112-1454 |
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