4 research outputs found
Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter
Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcription initiation in several promoters. Here, we use Langevin molecular dynamic simulations based on the Peyrard-Bishop-Dauxois nonlinear model of DNA (PBD LMD) to analyze the strand separation (bubble) dynamics of 80-bp-long promoter DNA sequences. We derive three dynamic criteria, bubble probability, bubble lifetime, and average strand separation, to characterize bubble formation at the transcriptional start sites of eight mammalian gene promoters. We observe that the most stable dsDNA openings do not necessarily coincide with the most probable openings and the highest average strand displacement, underscoring the advantages of proper molecular dynamic simulations. The dynamic profiles of the tested mammalian promoters differ significantly in overall profile and bubble probability, but the transcriptional start site is often distinguished by large (longer than 10 bp) and long-lived transient openings in the double helix. In support of these results are our experimental transcription data demonstrating that an artificial bubble-containing DNA template is transcribed bidirectionally by human RNA polymerase alone in the absence of any other transcription factors
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