Direct repair of 3,N[superscript 4]-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase
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Samson_Direct repair.pdf
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Author(s)
Fu, Dragony
Samson, Leona D
Date Issued
November 2011
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.
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Author's final manuscript
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.
MIT Department
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
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DOI of Published Version
https://doi.org/10.1016/j.dnarep.2011.10.004
