Register Shifts in Uracil-Damaged DNA
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Mentor Information
Dr. Arjan van der Vaart
Description
Uracil is a highly mutagenic and common lesion of DNA, which is caused by misincorporation or spontaneous deaminating of cytosine. Uracil will spontaneously base flip, breaking its Watson-Crick hydrogen bonds and base stacking and leaving the helix stack. It was previously observed that in rare cases, base flipping of uracil can be accompanied by a register shift, which sterically blocks the uracil from flipping back into the helix. To quantify the propensity of register shifts, I performed molecular dynamic simulations of 32 DNA sequences with central uracil-containing motifs. In these simulations, uracil was artificially flipped extrahelically toward either the major or minor groove. I confirmed wide occurrence of register shifts and characterized structural effects. This study shows that register shifts most commonly occur for 3’ cytosines on the uracil strand. Implications for DNA repair are discussed to prevent uracil-induced diseases including cancer.
Register Shifts in Uracil-Damaged DNA
Uracil is a highly mutagenic and common lesion of DNA, which is caused by misincorporation or spontaneous deaminating of cytosine. Uracil will spontaneously base flip, breaking its Watson-Crick hydrogen bonds and base stacking and leaving the helix stack. It was previously observed that in rare cases, base flipping of uracil can be accompanied by a register shift, which sterically blocks the uracil from flipping back into the helix. To quantify the propensity of register shifts, I performed molecular dynamic simulations of 32 DNA sequences with central uracil-containing motifs. In these simulations, uracil was artificially flipped extrahelically toward either the major or minor groove. I confirmed wide occurrence of register shifts and characterized structural effects. This study shows that register shifts most commonly occur for 3’ cytosines on the uracil strand. Implications for DNA repair are discussed to prevent uracil-induced diseases including cancer.
