Dataset Information

DNA sequence context conceals ?-anomeric lesions.

ABSTRACT: DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an ?-anomeric adenosine (?A) flanked by cytosines (5'C?AC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'C?AG-3' motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5'C?AG-3' core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total R(X) <5.3%). The ?A base is intrahelical, in a reverse Watson-Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5'C?AC-3' core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5'C?AC-3' sequence. The improved stacking of the 5'C?AG-3' core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV.

SUBMITTER: Johnson CN

PROVIDER: S-EPMC3479675 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DNA sequence context conceals α-anomeric lesions.

Johnson Christopher N CN Spring Alexander M AM Desai Sunil S Cunningham Richard P RP Germann Markus W MW

Journal of molecular biology 20111229 3

DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an α-anomeric adenosine (αA) flanked by cytosines (5'CαAC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'CαAG-3' motif exhibits unique substrate properties. How ...[more]

PMID: 22227386

Similar Datasets

Project description:One way to better understand the structure in DNA is by learning to predict the sequence. Here, we trained a model to predict the missing base at any given position, given its left and right flanking contexts. Our best-performing model was a neural network that obtained an accuracy close to 54% on the human genome, which is 2% points better than modelling the data using a Markov model. In likelihood-ratio tests, the neural network performed significantly better than any of the alternative models by a large margin. We report on where the accuracy was obtained, first observing that the performance appeared to be uniform over the chromosomes. The models performed best in repetitive sequences, as expected, although their performance far from random in the more difficult coding sections, the proportions being ~70:40%. We further explored the sources of the accuracy, Fourier transforming the predictions revealed weak but clear periodic signals. In the human genome the characteristic periods hinted at connections to nucleosome positioning. We found similar periodic signals in GC/AT content in the human genome, which to the best of our knowledge have not been reported before. On other large genomes similarly high accuracy was found, while lower predictive accuracy was observed on smaller genomes. Only in the mouse genome did we see periodic signals in the same range as in the human genome, though weaker and of a different type. This indicates that the sources of these signals are other or more than nucleosome arrangement. Interestingly, applying a model trained on the mouse genome to the human genome resulted in a performance far below that of the human model, except in the difficult coding regions. Despite the clear outcomes of the likelihood-ratio tests, there is currently a limited superiority of the neural network methods over the Markov model. We expect, however, that there is great potential for better modelling DNA using different neural network architectures.

Dataset Information

DNA sequence context conceals ?-anomeric lesions.

Publications

DNA sequence context conceals α-anomeric lesions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets