Biology Reference
In-Depth Information
accomplished by insertion of a particular wedge residue that senses the topog-
raphy of the minor groove and pauses either to check for damage at random
locations or in response to subtle deformations of the DNA helix.
V. Concluding Remarks
Advances in the structural biology and biochemistry of glycosylases have
led to a better understanding of how these complex enzymes recognize and
excise damaged bases. Based on current
in vitro
studies, we can speculate on
the mechanisms of specific lesion recognition. However, despite the vast
knowledge gained, several unanswered questions still remain. For instance,
we know that the Fpg/Nei family members recognize a broad range of sub-
strates but it is not clear how these enzymes discriminate among each of these
lesions and how they distinguish these from undamaged bases. Moreover, as
some glycosylases are active at different times in the cell cycle and interact with
a number of protein partners, how are these enzymes involved in processes
such as DNA replication or transcription? Additionally, it remains difficult to
classify certain members of the Fpg/Nei family under a specific subfamily. For
example, even though members of the Fpg/Nei family of proteins are struc-
turally similar, some elements such as the intercalation triad present in NEIL1
and MvNei1 suggest that these members could be classified under the Fpg
subfamily rather than the Nei subfamily after which they were originally
named. Many aspects of phylogenetic characterization, lesion recognition,
substrate specificities, and the biological functions of this glycosylase family
still remain to be elucidated.
Acknowledgments
We would like to thank Minmin Liu, Drs. Scott Kathe, St
ยด
phanie Duclos, and Ramiro
Barrantes-Reynolds for their helpful discussions. Dr. Andrew Dunn performed the single molecule
studies in our laboratory in collaboration with Dr. David Warshaw. This work was supported by
NIH/NCI P01 CA098993 (S. S. W., PI).
References
1. Chetsanga CJ, Lindahl T. Release of 7-methylguanine residues whose imidazole rings have
been opened from damaged DNA by a DNA glycosylase from
Escherichia coli
.
Nucleic Acids
Res
1979;
:3673-84.
2. Boiteux S, O'Connor TR, Laval J. Formamidopyrimidine-DNA glycosylase of
Escherichia
coli
: cloning and sequencing of the fpg structural gene and overproduction of the protein.
EMBO J
1987;
6
:3177-83.
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