Quinone methides (QMs) are a class of transient electrophilic intermediates that are formed in vivo from the metabolism of various compounds such as mitomycin C, tamoxifen, and butylated hydroxytoluene. Bifunctional QMs, capable of crosslinking DNA due to the presence of two electrophiles, alkylate DNA by forming both reversible and irreversible adducts. The formation of reversible adducts extends the effective lifetime of QMs. A bifunctional QM conjugated to the intercalator acridine (bisQMAc) was observed to migrate along duplex DNA by means of its dynamic alkylation.  This process was observed for naked DNA that did not contain the histone proteins that package DNA in cells.  For DNA to fit within the confines of a cell nucleus, it must be wrapped around octamers of histone proteins to form nucleosome core particles (NCPs).  The compaction in NCPs has now been found to protect DNA against reaction of bisQMAc. Conversely, DNA alkylation by bisQMAc impedes assembly of DNA into NCPs.  The histone proteins also serve as a target for QM alkylation, as bisQMAc reacts to form DNA- protein crosslinks within NCPs.  BisQMAc was observed to alkylate a limited number of sites on the histones, primarily in their hydrophobic regions.  BisQMAc’s intrinsic reversible chemistry permitted its transfer from a covalent adduct on DNA to a covalent adduct on the histones.  Transfer of bisQMAc between DNA and protein, along with its dynamic migration in DNA, may pose challenges for cells as they attempt to repair the adducts formed by QMs. Preliminary evidence suggests that a bisQMAc DNA crosslink does not inhibit DNA polymerases as they process damaged DNA. Future investigations will seek to further characterize primer extension of damaged DNA by polymerases, as well examine repair of bisQMAc by the nucleotide excision repair enzymes.<br/>

Repair and processing of DNA lesions induced by a dynamic electrophile

256th National Meeting (2018)

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