Register-Shifted Structures in Uracil:Adenine and Uracil:Guanine Base-Paired DNA

Register-shifted structures in uracil-damaged dsDNA greatly extend lesion exposure by blocking the base-flipped uracil from re-entering the helix stack. Molecular dynamics simulations were performed to assess the occurrence of register-shifted structures in U:A and U:G base-paired DNA for different sequence motifs and uracil base-flipping directions. Register-shifted structures were relatively common: significant populations were seen in 49 of 128 simulated sequences. They were about equally prevalent in U:A and U:G sequences, but uracil was preferentially flipped toward the major groove in U:A sequences and toward the minor groove in U:G sequences. The register-shifted base pair in U:G sequences commonly involved T:G mismatches. The majority of register shifts occurred in the 3' direction, and a few sequences formed register shifts over 2 and 3 base pairs. Register-shifted structures primarily occurred for sequences with UT motifs, which are known to be repaired slowly.