Nucleic Acids Research, Vol 27, Issue 15 3197-3204, Copyright © 1999 by Oxford University Press
CL Chepanoske, SL Porello, T Fujiwara, H Sugiyama and SS David
The Escherichia coli adenine glycosylase MutY is involved in the repair of
7,8-dihydro-8-oxo-2"-deoxyguanosine (OG):A and G:A mispairs in DNA. Our
approach toward understanding recognition and processing of DNA damage by
MutY has been to use substrate analogs that retain the recognition
properties of the substrate mispair but are resistant to the glycosylase
activity of MutY. This approach provides stable MutY- DNA complexes that
are amenable to structural and biochemical characterization. In this work,
the interaction of MutY with the 2"- deoxyadenosine analogs
2"-deoxy-2"-fluoroadenosine (FA), 2"- deoxyaristeromycin (R) and
2"-deoxyformycin A (F) was investigated. MutY binds to duplexes containing
the FA, R or F analogs opposite G and OG within DNA with high affinity;
however, no enzymatic processing of these duplexes is observed. The
specific nature of the interaction of MutY with an OG:FA duplex was
demonstrated by MPE-Fe(II) hydroxyl radical footprinting experiments which
showed a nine base pair region of protection by MutY surrounding the
mispair. DMS footprinting experiments with an OG:A duplex revealed that a
specific G residue located on the OG-containing strand was protected from
DMS in the presence of MutY. In contrast, a G residue flanking the
substrate analogs R, F or FA was observed to be hypersensitive to DMS in
the presence of MutY. These results suggest a major conformational change
in the DNA helix upon binding of MutY that exposes the substrate analog-
containing strand. This finding is consistent with a nucleotide flipping
mechanism for damage recognition by MutY. This work demonstrates that
duplex substrates for MutY containing FA, R or F instead of A are excellent
substrate mimics that may be used to provide insight into the recognition
by MutY of damaged and mismatched base pairs within DNA.
ARTICLES
Substrate recognition by Escherichia coli MutY using substrate analogs
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
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