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Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase.

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(6)-ethenoadenine (?A) and 3,N(4)-ethenocytosine (?C) with high affinity, only ?A can be excised to initiate base excision repair. Here, we discover that the human AlkB homolog 2 (ALKBH2) dioxygenase enzyme catalyzes direct reversal of ?C 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 ?C specifically blocks ALKBH2-catalyzed repair of ?C but not that of methylated ALKBH2 substrates. These results identify human ALKBH2 as a repair enzyme for mutagenic ?C lesions and highlight potential consequences for substrate-binding overlap between the base excision and direct reversal DNA repair pathways.

SUBMITTER: Fu D

PROVIDER: S-EPMC3253959 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase.

Fu Dragony D Samson Leona D LD

DNA repair 20111111 1

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(6)-ethenoadenine (ɛA) and 3,N(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 D ...[more]

PMID: 22079122

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