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Register-Shifted Structures in Uracil:Adenine and Uracil:Guanine Base-Paired DNA
Sang T Le Phan1, Emmanuel E Eni1, Maria S Roallos1
1Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33629, United States.
Abstract:
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.
Insights
Register-shifted DNA structures prolong uracil lesion exposure by hindering repair. These structures are common in uracil-damaged DNA, particularly in UT motifs, impacting DNA repair mechanisms.
Area of Science:
- Molecular Biology
- Biophysics
- Computational Chemistry
Background:
- Uracil in DNA, often resulting from cytosine deamination, poses a significant genotoxic risk.
- Register-shifted DNA structures are implicated in extending the persistence of uracil lesions.
- Understanding the formation and prevalence of these structures is crucial for DNA repair insights.
Purpose of the Study:
- To investigate the occurrence and characteristics of register-shifted structures in uracil-damaged double-stranded DNA (dsDNA).
- To assess the influence of sequence motifs and uracil base-flipping direction on register shift formation.
- To correlate register shift prevalence with known DNA repair rates.
Main Methods:
- Utilized molecular dynamics (MD) simulations to model DNA structures.
- Simulated uracil:adenine (U:A) and uracil:guanine (U:G) base pairs within various DNA sequence contexts.
- Analyzed the frequency, directionality, and base-pairing interactions of register-shifted structures.
Main Results:
- Register-shifted structures were observed in a significant proportion (49/128) of simulated sequences.
- These structures were similarly prevalent in U:A and U:G pairings.
- Uracil preferentially flipped towards the major groove in U:A and minor groove in U:G pairings; T:G mismatches were common in U:G register shifts.
- Most shifts occurred in the 3' direction, with some extending over multiple base pairs.
- Register shifts were most frequent in sequences containing uracil-thymine (UT) motifs, which are repaired slowly.
Conclusions:
- Register-shifted structures are a common structural motif in uracil-damaged DNA, contributing to extended lesion exposure.
- The formation of these structures is influenced by sequence context and the direction of uracil base flipping.
- The prevalence of register shifts in slowly repaired UT motifs suggests a role in modulating DNA repair efficiency and potentially contributing to mutagenesis.
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