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Separation-of-function mutants unravel the dual-reaction mode of human 8-oxoguanine DNA glycosylase.

Authors :
Dalhus B
Forsbring M
Helle IH
Vik ES
Forstrøm RJ
Backe PH
Alseth I
Bjørås M
Source :
Structure (London, England : 1993) [Structure] 2011 Jan 12; Vol. 19 (1), pp. 117-27.
Publication Year :
2011

Abstract

7,8-Dihydro-8-oxoguanine (8oxoG) is a major mutagenic base lesion formed when reactive oxygen species react with guanine in DNA. The human 8oxoG DNA glycosylase (hOgg1) recognizes and initiates repair of 8oxoG. hOgg1 is acknowledged as a bifunctional DNA glycosylase catalyzing removal of the damaged base followed by cleavage of the backbone of the intermediate abasic DNA (AP lyase/β-elimination). When acting on 8oxoG-containing DNA, these two steps in the hOgg1 catalysis are considered coupled, with Lys249 implicated as a key residue. However, several lines of evidence point to a concurrent and independent monofunctional hydrolysis of the N-glycosylic bond being the in vivo relevant reaction mode of hOgg1. Here, we present biochemical and structural evidence for the monofunctional mode of hOgg1 by design of separation-of-function mutants. Asp268 is identified as the catalytic residue, while Lys249 appears critical for the specific recognition and final alignment of 8oxoG during the hydrolysis reaction.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1878-4186
Volume :
19
Issue :
1
Database :
MEDLINE
Journal :
Structure (London, England : 1993)
Publication Type :
Academic Journal
Accession number :
21220122
Full Text :
https://doi.org/10.1016/j.str.2010.09.023