Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase
Exocyclic ethenobases are highly mutagenic DNA lesions strongly implicated in inflammation and vinyl chloride-induced carcinogenesis. While the alkyladenine DNA glycosylase, AAG (or MPG), binds the etheno lesions 1,N[superscript 6]-ethenoadenine (ɛA) and 3,N[superscript 4]-ethenocytosine (ɛC) with h...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99507 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1826216440652365824 |
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| author | Fu, Dragony Samson, Leona D |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Fu, Dragony Samson, Leona D |
| author_sort | Fu, Dragony |
| collection | MIT |
| description | Exocyclic ethenobases are highly mutagenic DNA lesions strongly implicated in inflammation and vinyl chloride-induced carcinogenesis. While the alkyladenine DNA glycosylase, AAG (or MPG), binds the etheno lesions 1,N[superscript 6]-ethenoadenine (ɛA) and 3,N[superscript 4]-ethenocytosine (ɛC) with high affinity, only ɛA can be excised to initiate base excision repair. Here, we discover that the human AlkB homolog 2 (ALKBH2) dioxygenase enzyme catalyzes direct reversal of ɛC lesions in both double- and single-stranded DNA with comparable efficiency to canonical ALKBH2 substrates. Notably, we find that in vitro, the non-enzymatic binding of AAG to ɛC specifically blocks ALKBH2-catalyzed repair of ɛC but not that of methylated ALKBH2 substrates. These results identify human ALKBH2 as a repair enzyme for mutagenic ɛC lesions and highlight potential consequences for substrate-binding overlap between the base excision and direct reversal DNA repair pathways. |
| first_indexed | 2024-09-23T16:47:43Z |
| format | Article |
| id | mit-1721.1/99507 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:47:43Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/995072022-10-03T08:19:54Z Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase Fu, Dragony Samson, Leona D Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Fu, Dragony Samson, Leona D. Exocyclic ethenobases are highly mutagenic DNA lesions strongly implicated in inflammation and vinyl chloride-induced carcinogenesis. While the alkyladenine DNA glycosylase, AAG (or MPG), binds the etheno lesions 1,N[superscript 6]-ethenoadenine (ɛA) and 3,N[superscript 4]-ethenocytosine (ɛC) with high affinity, only ɛA can be excised to initiate base excision repair. Here, we discover that the human AlkB homolog 2 (ALKBH2) dioxygenase enzyme catalyzes direct reversal of ɛC lesions in both double- and single-stranded DNA with comparable efficiency to canonical ALKBH2 substrates. Notably, we find that in vitro, the non-enzymatic binding of AAG to ɛC specifically blocks ALKBH2-catalyzed repair of ɛC but not that of methylated ALKBH2 substrates. These results identify human ALKBH2 as a repair enzyme for mutagenic ɛC lesions and highlight potential consequences for substrate-binding overlap between the base excision and direct reversal DNA repair pathways. American Cancer Society (Postdoctoral Fellowship 116155-PF-08-255-01-GMC) National Institutes of Health (U.S.) (Grant CA055042) National Institutes of Health (U.S.) (Grant ES002109) 2015-10-29T17:02:16Z 2015-10-29T17:02:16Z 2011-11 2011-10 Article http://purl.org/eprint/type/JournalArticle 15687864 http://hdl.handle.net/1721.1/99507 Fu, Dragony, and Leona D. Samson. “Direct Repair of 3,N[superscript 4]-Ethenocytosine by the Human ALKBH2 Dioxygenase Is Blocked by the AAG/MPG Glycosylase.” DNA Repair 11, no. 1 (January 2012): 46–52. https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.1016/j.dnarep.2011.10.004 DNA Repair Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Fu, Dragony Samson, Leona D Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title | Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title_full | Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title_fullStr | Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title_full_unstemmed | Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title_short | Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| title_sort | direct repair of 3 n superscript 4 ethenocytosine by the human alkbh2 dioxygenase is blocked by the aag mpg glycosylase |
| url | http://hdl.handle.net/1721.1/99507 https://orcid.org/0000-0002-7112-1454 |
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