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Uncovering universal rules governing the selectivity of the archetypal DNA glycosylase TDG [Biophysics and Computational Biology]

The most prominent epigenetic modification in mammalian genomes is cytosine methylation at position 5 on the pyrimidine ring. Thymine DNA glycosylase (TDG) plays a central role in the pathways for 5-methyl cytosine removal and thus influences gene silencing, stem cell differentiation, and alterations in normal development. Additionally, methylation abnormalities in DNA are often observed in diseases, specifically cancer. Here we examine the mechanisms by which TDG detects, extrudes, and excises modified bases in DNA. Using path-sampling methodologies, we compute minimum free energy paths for TDG base extrusion. The computed paths reveal a unique mechanism underpinning TDG selectivity for DNA lesions or modified bases, which involves DNA sculpting, global protein dynamics, conformational gating, and specific protein–nucleic acid interactions.

Authors:   Thomas Dodd; Chunli Yan; Bradley R. Kossmann; Kurt Martin; Ivaylo Ivanov
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   23
Year:   2018
Pages:   5974
DOI:   10.1073/pnas.1803323115
Publication date:   05-Jun-2018
Facts, background information, dossiers
  • DNA
  • selectivity
  • cytosine
  • bases
  • thymine
  • stem cell differentiation
  • pyrimidine
  • methylation
  • genomes
  • gene silencing
  • Energy
  • diseases
  • computational biology
  • cancer
More about Proceedings of the National Academy of Sciences
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