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Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase

Author(s)
Fu, Dragony; Samson, Leona D.
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Abstract
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.
Date issued
2011-11
URI
http://hdl.handle.net/1721.1/99507
Department
David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Center for Environmental Health Sciences; Massachusetts Institute of Technology. Department of Biological Engineering
Journal
DNA Repair
Publisher
Elsevier
Citation
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.
Version: Author's final manuscript
ISSN
15687864

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