Structural analysis of hypoxanthine mutagenicity using DNA polymerase β and η

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Hawkins, Michael Andrew

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Cellular life is precarious. Dangers abound for a cell’s DNA, from both external and internal factors, and maintaining genomic integrity is crucial for cell survival. Oxidative damage, from reactive oxygen/nitrogen species, can cause deamination of adenine, producing hypoxanthine. Hypoxanthine (Hx) is the nucleobase in inosine and plays a role in the genetic disorder Lesch-Nyhan Syndrome. Crucially, hypoxanthine has the potential to be mutagenic due to its ability to pair with cytosine. Hypoxanthine can also pair with thymine, but we propose that Hx preferentially interacts with cytosine which can lead to a potential transition mutation (dA to dG). Our structural data indicates that cytosine is indeed the preferred bonding partner for Hx. The crystal structures of DNA polymerase beta and eta complexed with DNA containing Hx and incoming nonhydrolyzable dCTP and dTTP shows how the dCTP is in a better position for the nucleotidyl transfer reaction. This study provides a better understanding of the detailed molecular interactions underlying this potentially mutagenic DNA lesion.


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