3 research outputs found
DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases
Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA
motif whose expansion is associated with a large number of human diseases. The
driving molecular mechanisms of the TRS ongoing dynamic expansion across
generations and within tissues and its influence on genomic DNA functions are
not well understood. Here we report results for a novel and notable collective
breathing behavior of genomic DNA of tandem TRS, leading to propensity for large
local DNA transient openings at physiological temperature. Our Langevin
molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations
demonstrate that the patterns of openings of various TRSs depend specifically on
their length. The collective propensity for DNA strand separation of repeated
sequences serves as a precursor for outsized intermediate bubble states
independently of the G/C-content. We report that repeats have the potential to
interfere with the binding of transcription factors to their consensus sequence
by altered DNA breathing dynamics in proximity of the binding sites. These
observations might influence ongoing attempts to use LMD and MCMC simulations
for TRS–related modeling of genomic DNA functionality in elucidating the
common denominators of the dynamic TRS expansion mutation with potential
therapeutic applications
The TRS expansion has an effect on the DNA bubble spectrum.
<p>EPBD based LMD simulations have been conducted on the: a)
(CAG.CTG)<sub>45</sub> repeats and healthy (CAG.CTG)<sub>10</sub>
repeats with 30 bp flanking huntington gene sequence; b)
(GAA.TTC)<sub>120</sub> and (GAA.TTC)<sub>6</sub> MRS that are
embedded in 50 bp frataxin gene sequence; c) (CGG.GCC)<sub>240</sub> and
(CGG.GCC)<sub>20</sub> repeats together with 50 bp FMR1 gene
flanking sequence. The y-axis represents the length of the bubbles in
bp; the x-axis represents the number of the base pairs; the color axis
gives the bubble duration in psec. The brackets above the panels denote
the repeated sequence; red arrows- the largest and long-lived base-pairs
openings.</p
Accumulation of (GAA.TTC) repeats leads to changes in local DNA breathing.
<p>BAD criteria are used to describe and compare the local base pair
breathing of DNA sequences with different numbers of (GAA.TTC) repeats
embedded within the frataxin gene [B7] promoter sequence. a)
BAD coordinates [Ã…] are calculated with EPBD based MCMC
simulations for sequence inserts with different numbers of repeats:
(GAA.TTC)<sub>6</sub>-black line, (GAA.TTC)<sub>45</sub>-red line,
and (GAA.TTC)<sub>120</sub>-blue line. The position of the flanking
sequence (fl) is shown above the panel. b) BAD coordinates for a
randomized sequence with the same number of base pairs and G+C
content as the (GAA.TTC)<sub>41</sub> sequence. The random sequence (red
line) is missing the synchronized average base pair openings behavior of
the symmetric (GAA.TTC)<sub>41</sub> (blue line). The nucleotide
position is shown on the horizontal. The BAD coordinates are shown on
the vertical in [Ã…].</p