4.7 Article

Hg(II) Binding to Thymine Bases in DNA

Journal

INORGANIC CHEMISTRY
Volume 60, Issue 10, Pages 7442-7452

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.1c00735

Keywords

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Funding

  1. Natural Sciences and Engineering Research Council of Canada (NSERC)
  2. Innovation and Science Fund of Saskatchewan
  3. Canada Foundation for Innovation John Evans Leader's Fund Award
  4. Canada Research Chairs
  5. Dr. Rui Feng Scholarship
  6. US Department of Energy Office of Science [DE-SC0007173]
  7. U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
  8. DOE Office of Biological and Environmental Research
  9. National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
  10. U.S. Department of Energy (DOE) [DE-SC0007173] Funding Source: U.S. Department of Energy (DOE)

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Research shows that Hg(II) can directly bind to DNA, forming interstrand cross-links, with the energetically preferred mode of binding to thymine being through N3. Using 1-methylthymine as a model, it is found that the bis-thymine coordination of Hg(II) provides a highly characteristic X-ray spectroscopic signature.
The compounds of mercury can be highly toxic and can interfere with a range of biological processes, although many aspects of the mechanism of toxicity are still obscure or unknown. One especially intriguing property of Hg(II) is its ability to bind DNA directly, making interstrand cross-links between thymine nucleobases in AT-rich sequences. We have used a combination of small molecule X-ray diffraction, X-ray spectroscopies, and computational chemistry to study the interactions of Hg(II) with thymine. We find that the energetically preferred mode of thymine binding in DNA is to the N3 and predict only minor distortions of the DNA structure on binding one Hg(II) to two cross-adjacent thymine nucleotides. The preferred geometry is predicted to be twisted away from coplanar through a torsion angle of between 32 and 43 degrees. Using 1-methylthymine as a model, the bis-thymine coordination of Hg(II) is found to give a highly characteristic X-ray spectroscopic signature that is quite distinct from other previously described biological modes of binding of Hg(II). This work enlarges and deepens our view of significant biological targets of Hg(II) and demonstrates tools that can provide a characteristic signature for the binding of Hg(II) to DNA in more complex matrices including intact cells and tissues, laying the foundation for future studies of mechanisms of mercury toxicity.

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