The role of methylation in the intrinsic dynamics of B- and Z-DNA

Nuri A. Temiz, Duncan E. Donohue, Albino Bacolla, Brian T. Luke, Jack R. Collins

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Methylation of cytosine at the 5-carbon position (5mC) is observed in both prokaryotes and eukaryotes. In humans, DNA methylation at CpG sites plays an important role in gene regulation and has been implicated in development, gene silencing, and cancer. In addition, the CpG dinucleotide is a known hot spot for pathologic mutations genome-wide. CpG tracts may adopt left-handed Z-DNA conformations, which have also been implicated in gene regulation and genomic instability. Methylation facilitates this B-Z transition but the underlying mechanism remains unclear. Herein, four structural models of the dinucleotide d(GC)5 repeat sequence in B-, methylated B-, Z-, and methylated Z-DNA forms were constructed and an aggregate 100 nanoseconds of molecular dynamics simulations in explicit solvent under physiological conditions was performed for each model. Both unmethylated and methylated B-DNA were found to be more flexible than Z-DNA. However, methylation significantly destabilized the BII, relative to the BI, state through the Gp5mC steps. In addition, methylation decreased the free energy difference between B- and Z-DNA. Comparisons of α/γ backbone torsional angles showed that torsional states changed marginally upon methylation for B-DNA, and Z-DNA. Methylation-induced conformational changes and lower energy differences may contribute to the transition to Z-DNA by methylated, over unmethylated, B-DNA and may be a contributing factor to biological function.

Original languageEnglish (US)
Article numbere35558
JournalPloS one
Volume7
Issue number4
DOIs
StatePublished - Apr 17 2012

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Z-DNA
Z-Form DNA
Methylation
methylation
B-DNA
B-Form DNA
Gene expression
DNA Methylation
Genes
molecular dynamics
Nucleic Acid Conformation
cytosine
Cytosine
energy
gene silencing
DNA methylation
cell aggregates
prokaryotic cells
Genomic Instability
Structural Models

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Temiz, N. A., Donohue, D. E., Bacolla, A., Luke, B. T., & Collins, J. R. (2012). The role of methylation in the intrinsic dynamics of B- and Z-DNA. PloS one, 7(4), [e35558]. https://doi.org/10.1371/journal.pone.0035558

The role of methylation in the intrinsic dynamics of B- and Z-DNA. / Temiz, Nuri A.; Donohue, Duncan E.; Bacolla, Albino; Luke, Brian T.; Collins, Jack R.

In: PloS one, Vol. 7, No. 4, e35558, 17.04.2012.

Research output: Contribution to journalArticle

Temiz, NA, Donohue, DE, Bacolla, A, Luke, BT & Collins, JR 2012, 'The role of methylation in the intrinsic dynamics of B- and Z-DNA', PloS one, vol. 7, no. 4, e35558. https://doi.org/10.1371/journal.pone.0035558
Temiz, Nuri A. ; Donohue, Duncan E. ; Bacolla, Albino ; Luke, Brian T. ; Collins, Jack R. / The role of methylation in the intrinsic dynamics of B- and Z-DNA. In: PloS one. 2012 ; Vol. 7, No. 4.
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