Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase |
| |
Authors: | Fu Dragony Samson Leona D |
| |
Institution: | Department of Biological Engineering, and Biology, Center for Environmental Health Sciences, David H. Koch Center for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States. |
| |
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,N6-ethenoadenine (?A) and 3,N4-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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|