David M Noll

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We have developed a new method for determining the DNA-binding specificity of proteins. In DIP-chip (DNA immunoprecipitation with microarray detection), protein.DNA complexes are isolated from an in vitro mixture of purified protein and naked genomic DNA. Whole-genome DNA microarrays are used to identify the protein-bound DNA fragments, and the sequence of(More)
Cellular DNA is susceptible to chemical modifications when exposed to various environmental agents, chemotherapeutic agents, or endogenous agents produced by cellular processes. The lesions produced by these chemical reactions can lead to mutations and/or cell death. Many of these lesions, in the form of base or phosphate modifications, occur on one or the(More)
O(6)-alkylguanine-DNA alkyltransferase (AGT), or O(6)-methylguanine-DNA methyltransferase (MGMT), prevents mutations and apoptosis resulting from alkylation damage to guanines. AGT irreversibly transfers the alkyl lesion to an active site cysteine in a stoichiometric, direct damage reversal pathway. AGT expression therefore elicits tumor resistance to(More)
MutY is an adenine-DNA glycosylase with specificity for mismatches involving 8-oxoguanine (oG.A) or guanine (G.A). In addition to a 25 kDa catalytic domain common to all members of its DNA glycosylase superfamily, MutY has a 14 kDa C-terminal domain. Sequence analyses suggest that this C-terminal domain is distantly related to MutT, a pyrophosphohydrolase(More)
Reaction of cellular DNA with environmental and chemotherapeutic agents can give rise to a variety of lesions including interstrand cross-links. Because interstrand cross-links can prevent DNA strand separation and thus DNA transcription and replication, they represent a serious impediment to cell survival. Cells have developed mechanisms to repair(More)
Interstrand DNA cross-links are the principal cytotoxic lesions produced by chemotherapeutic bifunctional alkylating agents. Using an N(4)C-ethyl-N(4)C interstrand DNA cross-link to mimic this class of clinically important cancer chemotherapeutic agents, we have characterized the repair, structure, and flexibility of DNA that contains this cross-link in two(More)
The preparation and physical properties of short DNA duplexes that contain a N(4)C-ethyl-N(4)C interstrand cross-link are described. Duplexes that contain an interstrand cross-link between mismatched C-C residues and duplexes in which the C residues of a -CG- or -GC- step are linked to give "staggered" interstrand cross-links were prepared using a novel(More)
Short DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link, C-C, were synthesized on controlled pore glass supports. Duplexes having two, three, or four A/T base pairs on either side of the C-C cross-link and terminating with a C(4) overhang at their 5'-ends were prepared. The cross-link was introduced using a convertible nucleoside approach.(More)
The DNA repair protein O(6)-alkylguanine alkyltransferase (AGT) is responsible for removing promutagenic alkyl lesions from exocyclic oxygens located in the major groove of DNA, i.e. the O(6) and O(4) positions of guanine and thymine. The protein carries out this repair reaction by transferring the alkyl group to an active site cysteine and in doing so(More)
A synthetic gene was constructed that encodes human DNA methylguanine methyltransferase (hMGMT). The synthetic gene was designed with a number of unique restriction sites to facilitate cassette mutagenesis and to reflect the preferences found among genes in Escherichia coli. Both the full-length gene and a gene for a functional variant (hMGMT delta C) that(More)