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

作者：Fu Dragony; Samson Leona D^*

来源：DNA Repair, 2012, 11(1): 46-52.

DOI：10.1016/j.dnarep.2011.10.004

• AAG
• AlkB
• ALKBH2
• DNA repair
• Ethenocytosine
• MPG

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 (epsilon A) and 3,N-4-ethenocytosine (epsilon C) with high affinity, only epsilon 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 epsilon 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 epsilon C specifically blocks ALKBH2-catalyzed repair of epsilon C but not that of methylated ALKBH2 substrates. These results identify human ALKBH2 as a repair enzyme for mutagenic epsilon C lesions and highlight potential consequences for substrate-binding overlap between the base excision and direct reversal DNA repair pathways.

• 出版日期2012-1-2