CH391L/S2013 Alesha Stewart Mar 20 2013
Structure of a DNA glycosylase searching for lesions- Banerjee A, Santos WL, Verdine GL
Background & Introduction
DNA glycosylases are proteins responsible for DNA damage recognition and repair [4]. These enzymes search entire genomes for single nucleobase lesions to initiate base excision repair. The ability of DNA glycosylase to seek and find damaged bases is a wonder of science, especially since there are only minor differences between impaired and unimpaired bases. Thermo energy fuels this efficient process, as no biochemical forms of energy are expended. Details concerning the function and execution of DNA glycosylase are still under investigation, but the article “The Structure of a DNA Glycosylase Searching for Lesions” intends to shed light on the subject [1].
In this study, the authors utilized a bacterial DNA glycosylase (Bacillus stearothermophilus MutM) that specifically associates with 8-oxoguanine (oxoG). OxoG is a form of DNA damage from reactive oxygen species, where guanine is oxidized. As a result, the lesion can cause mismatched base pairing or mutations leading to genome instability and cancer if the damage goes unrepaired [2]. There is an oxoG resistance pathway in bacteria to protect against such damage (the “GO” system). MutM is the component of the system responsible for excising oxoG:C base pairs [3].
When MutM binds to an oxoG DNA base it represents the lesion recognition complex (LRC), which was used to investigate the recognition and repair method Fig 1A. Images of the LRC indicated that MutM physically flips the oxidized nucleobase out from the DNA helix to position it into its active site Fig 1A. Extrahelical base excision is now believed to be a universal technique used for all DNA glycosylases [1].
The mechanism of how extrahelical base excision is executed, however, is still undetermined. There are three proposals previously considered to explain how DNA glycosylases search, find, and repair damaged nucleobases- 1) It actively extrudes every base from the DNA; 2) It detects damaged bases that were spontaneously extruded from the DNA; or 3) It identifies lesions and activates the extrusion from the DNA. The researchers focused on the latter option, intrahelical lesion recognition, as it is the most kinetically favorable [1].
