Finding needles in a basestack: recognition of mismatched base pairs in DNA by small molecules

Abstract

Mismatched (non-Watson-Crick) base pairs represent the most common type of DNA damage, as they are permanently formed in living cells due to erroneous insertion, deletion and misincorporation of bases. In vivo, they are readily recognised and repaired by the proteins of the DNA mismatch repair system, which identify the mismatch sites with high efficiency and fidelity. Notably, the last decades have witnessed the development of several chemically diverse families of small organic molecules and metal complexes that selectively bind to mismatched base pairs (and not to fully paired double-stranded DNA), much like the proteins of the mismatch repair system. This review focuses on these DNA mismatch-binding ligands, with an emphasis on their (often unusual) binding modes, as well as on the similarities and differences between the different classes of mismatch binders. Also discussed are the potential bioanalytical and therapeutic applications of mismatch-binding ligands.

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

“…This site is most easily unwound to accommodate the intercalator and represents just one of many noncanonical structures of DNA that preferentially bind intercalators. Other examples include abasic sites, mismatched base pairs and regions containing extrahelical bases [57][58][59][60] . Thus, there is a potential for a mobile crosslinker to scan over DNA for damage by walking along canonical structures and ultimately accumulating at aberrant sites that offer the most favourable thermodynamics for alkylation and intercalation.…”

Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells

“…The Rh-PPO mechanism is reminiscent of lesion-specific DNA glycosylases that probe destabilized regions of the genome and, upon binding, flip the mismatched base into the enzyme active site (31,32). Indeed, the first-generation metalloinsertor, similar to a glycosylase, was able to photochemically cleave DNA at a mismatch site (31,33).…”

“…Indeed, the first-generation metalloinsertor, similar to a glycosylase, was able to photochemically cleave DNA at a mismatch site (31,33). A mismatch bound by a glycosylase typically would undergo further processing such as base excision and repair (18).…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…Some colon cancers may show defects in the DNA mismatch-repair machinery and this feature may be valuable as a diagnostic or therapeutic strategy by targeting such mismatches. 69 Some small molecules, including metal-based anticancer agents were shown to interact with mismatched DNA bases. 69,70 The first report on an intercalating ruthenium metallodrug by Xray diffraction revealed insertion into the site of the A:A mismatch on the oligonucleotide 5'-(dCGGAAATTACCG)2-3' by expulsing both adenines, which then stacked with the ancillary metal-bound phenanthroline ligands ( Figure 3B).…”

“…69 Some small molecules, including metal-based anticancer agents were shown to interact with mismatched DNA bases. 69,70 The first report on an intercalating ruthenium metallodrug by Xray diffraction revealed insertion into the site of the A:A mismatch on the oligonucleotide 5'-(dCGGAAATTACCG)2-3' by expulsing both adenines, which then stacked with the ancillary metal-bound phenanthroline ligands ( Figure 3B). 71 In contrast to platinum anticancer agents binding to duplex DNA via the major groove, this ruthenium compound inserted in the minor groove.…”